WO2016107227A1

WO2016107227A1 - Pyrrole amide compound, preparation method therefor, and use thereof

Info

Publication number: WO2016107227A1
Application number: PCT/CN2015/090291
Authority: WO
Inventors: 李进; 李雪明; 窦登峰; 万金桥; 高剑; 穆云; 李才奎; 潘飞; 钟国庆; 胡晓; 刘绍军; 吕鹏
Original assignee: 成都先导药物开发有限公司
Priority date: 2014-12-29
Filing date: 2015-09-22
Publication date: 2016-07-07
Also published as: EP3241823B1; CN105801464A; CN105801464B; US10266489B2; JP2018503683A; EP3241823A4; US20170298016A1; EP3241823A1

Abstract

Disclosed are a pyrrole amide compound as represented in formula I, polymorphs thereof, or pharmaceutically acceptable salts, hydrates, or solvate compounds. The present invention has good deacetylase inhibitory activity. Additionally, the preparation method for the compound involves few steps and is easy to operate, safe, and environmentally friendly, produces high yields, and is suitable for industrial application.

Description

吡咯酰胺类化合物及其制备方法与用途Pyrrolamide compound and preparation method and use thereof

技术领域Technical field

本发明涉及一种吡咯酰胺类化合物及其制备方法与用途，具体涉及一种具有组蛋白去乙酰化酶抑制活性的吡咯酰胺类化合物及其制备方法与用途。The present invention relates to a pyrrolamide compound, a preparation method and use thereof, and particularly to a pyrrolamide compound having histone deacetylase inhibitory activity, a preparation method thereof and use thereof.

背景技术Background technique

在机体中控制细胞生长的基因失活是肿瘤发生的一个标志。引起基因失活的外遗传机制主要包括DNA甲基化，组蛋白乙酰化和染色质高级结构中其他成分的修饰，这些修饰改变染色质构型，导致基因转录调节发生变化，基因转录的失调引起细胞增殖失常，从而导致肿瘤产生。Inactivation of genes that control cell growth in the body is a hallmark of tumorigenesis. The epigenetic mechanisms that cause gene inactivation mainly include DNA methylation, histone acetylation, and modification of other components in the chromatin high-level structure. These modifications alter the chromatin configuration, leading to changes in gene transcriptional regulation, and dysregulation of gene transcription. Cell proliferation is abnormal, resulting in tumor production.

40多年前，Allfrey等就认识到组蛋白的乙酰化过程和真核细胞基因转录调控密切相关(Allfrey VG，Faulkner R，Mirsky AE.Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis[J].Proc Natl Acad Sci USA，1964，51：786-794)。组蛋白乙酰化对于真核细胞的转录调控起核心作用。组蛋白的乙酰化修饰发生在N-端进化保守的赖氨酸残基的ε-氨基上，在H3和H4上的修饰较H2A和H2B更为普遍，比较重要的乙酰化位点是H3上的Lys⁹和Lys¹⁴，以及H4上的Lys⁵，Lys⁸，Lys¹²及Lys¹⁶。HAT的乙酰化作用使组蛋白N端赖氨酸的氨基乙酰化，氨基上的正电荷被消除，DNA分子本身所带有的负电荷利于DNA构象的展开，核小体的结构变得松弛，有利于转录因子和协同转录活化子与DNA分子的接触，组蛋白乙酰化可以激活特定基因转录表达。相反的，组蛋白的去乙酰化作用不利于特定基因(如：Rb，p21，p27)的表达。组蛋白的乙酰化和去乙酰化成为特定基因表达的切换开关(Thiagalingam S，Cheng KH，Lee HJ，et al.Histonedeacetylases：unique players in shaping the epigenetic histone code[J].Ann N Y Acad Sci，2003，983：84-100)。More than 40 years ago, Allfrey et al. recognized that histone acetylation is closely related to eukaryotic gene transcriptional regulation (Allfrey VG, Faulkner R, Mirsky AE. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis [ J]. Proc Natl Acad Sci USA, 1964, 51: 786-794). Histone acetylation plays a central role in the transcriptional regulation of eukaryotic cells. The acetylation of histones occurs on the ε-amino group of the N-terminal evolutionarily conserved lysine residue. The modification on H3 and H4 is more common than H2A and H2B. The more important acetylation site is H3. Lys ⁹ and Lys ¹⁴ , and Lys ⁵ , Lys ⁸ , Lys ¹² and Lys ¹⁶ on H4. The acetylation of HAT causes the amino group of the N-terminal lysine of the histone to be acetylated, and the positive charge on the amino group is eliminated. The negative charge carried by the DNA molecule itself facilitates the unfolding of the DNA conformation, and the structure of the nucleosome becomes slack. Conducive to the contact of transcription factors and co-transcriptional activators with DNA molecules, histone acetylation can activate the transcriptional expression of specific genes. In contrast, histone deacetylation is not conducive to the expression of specific genes (eg, Rb, p21, p27). The acetylation and deacetylation of histones becomes a switch for specific gene expression (Thiagalingam S, Cheng KH, Lee HJ, et al. Histone deacetylases: unique players in shaping the epigenetic histone code [J]. Ann NY Acad Sci, 2003, 983:84-100).

组蛋白乙酰化作用受一对功能相互拮抗的蛋白酶组蛋白乙酰化转移酶(HATs)和组蛋白去乙酰化酶(HDACs)调控。在正常细胞中，这一对酶处于动态平衡状态。一般情况下，组蛋白乙酰化水平增强与基因转录活性增强有关，而乙酰化水平过低与基因表达抑制有关(Forsberg EC，Bresnick EH.Histone acetylation beyond promoters：long-range acetylation patterns in the chromatin world[J].Bioessays，2001，23(9)：820-830)。研究发现，HDAC过度表达并被转录因子募集，导致特定基因的不正常抑制，从而导致肿瘤和其他疾病；而抑制HDAC的活性将引起许多癌细胞的生长抑制和凋亡(Somech R，Izraeli S，J Simon A.Histone deacetylase inhibitors-a new tool to treat cancer[J].Cancer Treat Rev，2004，30(5)：461-472)。因此，HDAC已成为目前抗肿瘤药物研发领域最新和最热门的靶标。Histone acetylation is regulated by a pair of functionally antagonistic protease histone acetyltransferases (HATs) and histone deacetylases (HDACs). In normal cells, this pair of enzymes is in a state of dynamic equilibrium. In general, increased levels of histone acetylation are associated with increased transcriptional activity, while low levels of acetylation are associated with inhibition of gene expression (Forsberg EC, Bresnick EH. Histone acetylation beyond promoters: long-range acetylation patterns in the chromatin world [ J]. Bioessays, 2001, 23(9): 820-830). Studies have found that HDAC is overexpressed and recruited by transcription factors, leading to abnormal inhibition of specific genes, leading to tumors and other diseases; while inhibition of HDAC activity will cause growth inhibition and apoptosis of many cancer cells (Somech R, Izraeli S, J Simon A. Histone deacetylase inhibitors-a new tool to treat cancer [J]. Cancer Treat Rev, 2004, 30(5): 461-472). Therefore, HDAC has become the latest and most popular target in the field of anti-tumor drug research and development.

HDAC抑制剂，可抑制HDAC酶活性，其作用机制是通过抑制HDAC，阻断由于HDAC募集功能紊乱而导致的基因表达受抑，通过改变组蛋白的乙酰化程度来改变染色质结构，从而调控基因表达治疗癌症。它通过诱导肿瘤细胞的生长停滞、分化或凋亡对治疗血液***肿瘤和实体瘤疗效显著。HDAC抑制剂具有肿瘤特异性，对增殖和静止的变异细胞均有细胞毒作用，而正常细胞对它有10倍以上的耐受，不会引起正常细胞的生长停滞和凋亡。而且HDAC抑制剂临床用量远低于人体最大耐受量，对机体的毒性较低。HDAC抑制剂的开发利用已成为肿瘤治疗的一个新热点。HDAC inhibitors inhibit HDAC enzyme activity by inhibiting HDAC, blocking gene expression inhibition due to HDAC recruitment dysfunction, and altering staining by altering the degree of histone acetylation Quality structure, which regulates gene expression to treat cancer. It is effective in treating hematological tumors and solid tumors by inducing growth arrest, differentiation or apoptosis of tumor cells. HDAC inhibitors are tumor-specific and have cytotoxic effects on both proliferating and resting variant cells, whereas normal cells are more than 10 times more tolerant and do not cause normal cell growth arrest and apoptosis. Moreover, the clinical dose of HDAC inhibitors is much lower than the maximum tolerated dose of the human body, and the toxicity to the body is low. The development and utilization of HDAC inhibitors has become a new hot spot in cancer therapy.

目前，已经研究开发的HDAC抑制剂可分为五大类：(1)异羟肟酸类化合物，功能基团为羟肟酸，代表物有TSA、SAHA(Curtin ML，Garland RB，Heyman HR，et a1.Succinimide hydroxamic acids as potent inhibitors of histone deacetylase[J].Bioorg Med Chem Lett，2002，12(20)：2919-2923)，LAQ824(Atadja P，Hsu M，Kwon P，et a1.Moleculer and cellular basis for the anti-proliferative effects of the HDAC inhibitor LAQ824.Novartis Found Symp，2004，259：249-266)；(2)含2-氨基-8-氧-9，10-环氧癸酰基或不含有该基团的环四肽，如FK-228；(3)苯甲酰胺类化合物，代表物MS-275已进入临床研究；(4)短链脂肪酸类，如丁酸和苯丁酸；(5)其他类，该类HDAC抑制剂不具有一般HDAC的结构特征，但都含有抑制HDAC活性要求的一些或全部的结构亚单位。At present, HDAC inhibitors that have been researched and developed can be divided into five categories: (1) hydroxamic acid compounds, functional groups are hydroxamic acid, and representatives are TSA, SAHA (Curtin ML, Garland RB, Heyman HR, et A1.Succinimide hydroxamic acids as potent inhibitors of histone deacetylase [J]. Bioorg Med Chem Lett, 2002, 12(20): 2919-2923), LAQ824 (Atadja P, Hsu M, Kwon P, et a1. Moleculer and cellular basis For the anti-proliferative effects of the HDAC inhibitor LAQ824.Novartis Found Symp, 2004, 259: 249-266); (2) containing or not containing 2-amino-8-oxo-9,10-epoxydecanoyl Group of tetrapeptides, such as FK-228; (3) benzamides, the representative MS-275 has entered clinical research; (4) short-chain fatty acids, such as butyric acid and phenylbutyric acid; (5) other Classes, such HDAC inhibitors do not have the structural features of a general HDAC, but all contain some or all of the structural subunits that inhibit HDAC activity requirements.

例如，中国专利CN 103420917 A公开了一种含稠环结构的苯甲酰胺类化合物，如式A所示，对组蛋白去乙酰化酶抑制活性及在治疗恶性肿瘤及与分化和增殖相关疾病方面的应用；中国专利CN 103288728 A公开了一种萘甲酰胺衍生物，如式B所示，能够有效治疗蛋白激酶调节异常所引发的部分疾病；中国专利CN 103539695 A公开了一种取代二苯醚类组蛋白去乙酰化酶抑制剂，如式C所示；中国专利CN 103467359 A公开了一种含有吲哚的肉桂酰胺类组蛋白去乙酰化酶抑制剂，如式D所示；中国专利CN 102659630 A公开了异羟肟酸类化合物，如式E所示。For example, Chinese Patent No. WO 103420917 A discloses a benzamide compound having a fused ring structure, as shown in Formula A, for histone deacetylase inhibitory activity and in treating malignant tumors and diseases related to differentiation and proliferation. Application; Chinese Patent CN 103288728 A discloses a naphthylcarboxamide derivative, as shown in Formula B, which is effective for treating some diseases caused by abnormality of protein kinase regulation; Chinese Patent CN 103539695 A discloses a substituted diphenyl ether. a histone deacetylase inhibitor, as shown in Formula C; Chinese Patent CN 103467359 A discloses a cinnamamide-containing histone deacetylase inhibitor containing hydrazine, as shown in Formula D; Chinese Patent CN 102659630 A discloses a hydroxamic acid compound as shown in Formula E.

中国专利CN 102786458 A公开了一种吡咯甲酰胺衍生物，如式F所示，作为抗恶性肿瘤药物方面的应用，特别是在用于制备治疗乳腺癌、肺癌、胃癌药物方面的用途。Chinese patent CN 102786458 A discloses a pyrrolecarboxamide derivative, as shown in Formula F, for use as an anti-malignant drug, particularly for the preparation of a medicament for the treatment of breast cancer, lung cancer and gastric cancer.

R₁，R₂，R₃，R₄为：C1-C6直链或支链烷基，C3-C6环烷基；R ₁ , R ₂ , R ₃ , R ₄ are: a C1-C6 straight or branched alkyl group, a C3-C6 cycloalkyl group;

R₅，R₆同时或分别为：氢，C1-C6烷基；羟基，卤素，C1-C4烷氧基，硝酸酯基取代的C1-C6的烷基。R ₅ and R _{6 are} simultaneously or respectively: hydrogen, C1-C6 alkyl; hydroxy, halogen, C1-C4 alkoxy, nitrate-substituted C1-C6 alkyl.

目前，Merck公司研制的SAHA，是已经上市的组蛋白去乙酰化酶抑制剂，仅局限于对皮肤T细胞淋巴癌的治疗，对其他很多癌症的疗效并不明显。其他研发的HDAC抑制剂，在抗癌活性、毒副作用、亚型选择性等方面也存在一定的问题。因此，开发一种具有组蛋白去乙酰化酶抑制活性的新化合物具有十分重要的社会和经济意义。At present, the SAHA developed by Merck is a listed histone deacetylase inhibitor, which is limited to the treatment of cutaneous T-cell lymphoma, and is not effective for many other cancers. Other HDAC inhibitors developed have certain problems in anticancer activity, toxic side effects, and subtype selectivity. Therefore, the development of a novel compound having histone deacetylase inhibitory activity has important social and economic significance.

发明内容Summary of the invention

本发明的目的在于一种吡咯酰胺类化合物。The object of the invention is a pyrrolamide compound.

本发明提供的式Ⅰ所示的吡咯酰胺类化合物或其晶型、药学上可接受的盐、水合物或溶剂合物：The pyrrole amide compound of the formula I, or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, of the invention:

其中，among them,

R₁选自氢、羟基、氰基、卤素、羧基、C₁～C₆的烷基、C₁～C₆的烷氧基、C₂～C₆的酰胺基、C₂～C₆的氨酰基、C₃～C₆的杂环基、C₃～C₆的杂环烯基或苯氧基；R _{1 is} selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ amide, C ₂ -C ₆ ammonia An acyl group, a C ₃ -C ₆ heterocyclic group, a C ₃ -C ₆ heterocycloalkenyl group or a phenoxy group;

R₂选自氢、羟基、氰基、卤素、羧基、C₁～C₆的烷基、C₁～C₆的烷氧基、C₂～C₆的酰胺基、C₂～C₆的氨酰基、C₃～C₆的杂环基、C₃～C₆的杂环烯基、苯氧基、苯基或取代的苯基；R _{2 is} selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ amide, C ₂ -C ₆ ammonia An acyl group, a C ₃ -C ₆ heterocyclic group, a C ₃ -C ₆ heterocycloalkenyl group, a phenoxy group, a phenyl group or a substituted phenyl group;

R₃选自羟基、氨基取代的苯基、巯基或环氧酮基团；R _{3 is} selected from a hydroxyl group, an amino-substituted phenyl group, a fluorenyl group or an epoxy ketone group;

X选自

基团，m＝0、1、2或3，n＝0、1或2。X is selected from

A group, m = 0, 1, 2 or 3, n = 0, 1 or 2.

优选的，Preferably,

R₁选自氢、羟基、氰基、氟、氯、溴、羧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊烷基、己烷基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊烷氧基、己烷氧基、甲酰胺基、乙酰氨基、正丙酰胺基、异丙酰胺基、正丁酰胺基、异丁酰胺基、叔丁酰胺基、戊烷酰胺基、己烷酰胺基、甲氨酰基、乙氨酰基、正丙氨酰基、异丙氨酰基、正丁氨酰基、异丁氨酰基、叔丁氨酰基、戊氨酰基、己氨酰基、C₃的氮杂环基、C₄的氮杂环基、C₅的氮杂环基、C₆的氮杂环基、C₃的氮杂环烯基、C₄的氮杂环烯基、C₅的氮杂环烯基、C₆的氮杂环烯基或苯氧基；R _{1 is} selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentylene, hexyl Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, Acetylamino, n-propionamido, isopropylamide, n-butyryl, isobutyryl, t-butyryl, pentane amide, hexane amide, carbamoyl, acetylyl, n-alanyl , isopropylamino, n-butyryl, isobutyryl, tert-butyryl, pentyl, hexyl, aziridine of C ₃ , azacyclic of C ₄ , aza of C ₅ a cyclic group, a nitrogen heterocyclic group of C _{6 ,} an azacycloalkenyl group of C _{3 ,} an azacycloalkenyl group of C _{4 ,} an azacycloalkenyl group of C _{5 ,} an azacycloalkenyl group of C ₆ or a phenoxy group ;

R₂选自氢、羟基、氰基、氟、氯、溴、羧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊烷基、己烷基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊烷氧基、己烷氧基、甲酰胺基、乙酰氨基、正丙酰胺基、异丙酰胺基、正丁酰胺基、异丁酰胺基、叔丁酰胺基、戊烷酰胺基、己烷酰胺基、甲氨酰基、乙氨酰基、正丙氨酰基、异丙氨酰基、正丁氨酰基、异丁氨酰基、叔丁氨酰基、戊氨酰基、己氨酰基、C₃的氮杂环基、C₄的氮杂环基、C₅的氮杂环基、C₆的氮杂环基、C₃的氮杂环烯基、C₄的氮杂环烯基、C₅的氮杂环烯基、C₆的氮杂环烯基、苯氧基、苯基或取代的苯基；R _{2 is} selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentylene, hexyl Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, Acetylamino, n-propionamido, isopropylamide, n-butyryl, isobutyryl, t-butyryl, pentane amide, hexane amide, carbamoyl, acetylyl, n-alanyl , isopropylamino, n-butyryl, isobutyryl, tert-butyryl, pentyl, hexyl, aziridine of C ₃ , azacyclic of C ₄ , aza of C ₅ a cyclic group, a nitrogen heterocyclic group of C _{6 ,} an azacycloalkenyl group of C _{3 ,} an azacycloalkenyl group of C _{4 ,} an azacycloalkenyl group of C _{5 ,} an azacycloalkenyl group of C ₆ , a phenoxy group Phenyl or substituted phenyl;

R₁与R₂不同时为氢；When R _{1 is} different from R _{2 ,} it is hydrogen;

R₃选自羟基、氨基取代的苯基或巯基；R _{3 is} selected from a hydroxy group, an amino-substituted phenyl group or a fluorenyl group;

m＝1或2，n＝1或2。m=1 or 2, n=1 or 2.

优选的，式Ⅰ所示化合物为： Preferably, the compound of formula I is:

本发明的另一目的在于提供制备上述式Ⅰ所示吡咯酰胺类化合物的方法。Another object of the present invention is to provide a process for the preparation of the pyrrole amide compound of the above formula I.

本发明提供的一种制备式Ⅰ所示吡咯酰胺类化合物的方法，它的合成路线为： The invention provides a method for preparing a pyrrole amide compound of the formula I, which has the following synthetic route:

其中，Boc代表叔丁氧羰基；TFA代表三氟乙酸；Fmoc-Cl代表芴氧羰酰氯；HATU代表2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；DIEA代表N,N-二异丙基乙胺；DCM代表二氯甲烷；Wherein, Boc represents t-butoxycarbonyl; TFA represents trifluoroacetic acid; Fmoc-Cl represents oxocarbonyl chloride; HATU represents 2-(7-azobenzotriazole)-N,N,N',N'- Tetramethylurea hexafluorophosphate; DIEA stands for N,N-diisopropylethylamine; DCM stands for dichloromethane;

R₅选自卤素；R _{5 is} selected from halogen;

X选自

基团，m＝0、1、2或3，n＝0、1或2；X is selected from

a group, m = 0, 1, 2 or 3, n = 0, 1 or 2;

包括以下步骤：Includes the following steps:

a、化合物IM-4、氢氧化锂和醚类溶剂/水的混合溶剂，于20℃～30℃搅拌反应1h～6h后，除去有机溶剂，加水稀释，调节pH＝3～6，析出固体，过滤，得到固体；对固体进行水洗、干燥，得到N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-甲酸；a, compound IM-4, lithium hydroxide and ether solvent / water mixed solvent, stirring reaction at 20 ° C ~ 30 ° C for 1h ~ 6h, remove the organic solvent, diluted with water, adjust the pH = 3 ~ 6, precipitate solid, Filtration to obtain a solid; washing the solid with water and drying to give N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid;

所述化合物IM-4与氢氧化锂的摩尔比为1：(1～10)；所述化合物IM-4与混合溶剂的质量体积比为1：(7～20)(m：v)；所述混合溶剂中，醚类溶剂与水的体积比为(1～2)：1；The molar ratio of the compound IM-4 to lithium hydroxide is 1: (1 to 10); the mass to volume ratio of the compound IM-4 to the mixed solvent is 1: (7 to 20) (m: v); In the mixed solvent, the volume ratio of the ether solvent to water is (1 to 2): 1;

b、0℃～5℃下，将步骤a的N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-甲酸溶解于卤烃类溶剂中，加入三氟乙酸，于20℃～30℃搅拌反应2h～12h后，得到反应液；对反应液进行浓缩，得到黄色油状物，即为化合物IM-3；b, N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid of step a is dissolved in a halogen hydrocarbon solvent at 0 ° C to 5 ° C, and trifluoroacetic acid is added at 20 ° C. After stirring at ～30°C for 2h~12h, the reaction liquid is obtained; the reaction liquid is concentrated to obtain a yellow oil, which is compound IM-3;

所述N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-甲酸、卤烃类溶剂与三氟乙酸的质量体积比1：(5～20)：(2～10)(m：v：v)；The mass-to-volume ratio of the N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid, halocarbon solvent and trifluoroacetic acid is 1: (5-20): (2-10) ( m:v:v);

c、步骤b的化合物IM-3、碳酸钠、芴氧甲酰氯和醚类溶剂/水的混合溶剂，于20℃～30℃搅拌反应12h～16h后，加水稀释，调节pH＝1～3，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到化合物IM-2；c. The compound IM-3 of the step b, the mixed solvent of sodium carbonate, decanoyl chloride and ether solvent/water is stirred at 20 ° C to 30 ° C for 12 h to 16 h, diluted with water, and adjusted to pH = 1 to 3, Extraction of the ester solvent, combining the organic phase, drying the organic phase, filtering, and concentrating to obtain the compound IM-2;

所述化合物IM-3、碳酸钠与芴氧甲酰氯的摩尔比为1：(1～5)：(0.9～1.5)；所述化合物IM-3与混合溶剂的质量体积比为1：(10～25)；所述混合溶剂中，醚类溶剂与水的体积比为(1～2)：1；The molar ratio of the compound IM-3, sodium carbonate and decanoyl chloride is 1: (1 to 5): (0.9 to 1.5); the mass to volume ratio of the compound IM-3 to the mixed solvent is 1: (10) ～25); in the mixed solvent, the volume ratio of the ether solvent to water is (1 to 2): 1;

d、步骤c的化合物IM-2、O-(四氢-2H-吡喃-2-基)羟基胺、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、N,N-二异丙基乙胺和卤烃类溶剂，于25℃～30℃搅拌反应12h～16h后，加水稀释，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到粗品；粗品经柱层析纯化，得到化合物IM-1；d, compound IM-2 of step c, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, 2-(7-azobenzotriazole)-N,N,N',N '-Tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine and halogen hydrocarbon solvent, stirred at 25 ° C ~ 30 ° C for 12h ~ 16h, diluted with water, ester solvent extraction, combined organic The organic phase is dried, filtered and concentrated to obtain a crude product; the crude product is purified by column chromatography to give compound IM-1;

所述化合物IM-2、O-(四氢-2H-吡喃-2-基)羟基胺、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯与N,N-二异丙基乙胺的摩尔比为1：(1～2)：(1～2)：(2～4)；所述化合物IM-2与卤烃类溶剂的质量体积比为1：(9～20)(m：v)；The compound IM-2, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, 2-(7-azobenzotriazole)-N,N,N',N'-four The molar ratio of methyl urea hexafluorophosphate to N,N-diisopropylethylamine is 1: (1 to 2): (1 to 2): (2 to 4); the compound IM-2 and halogen The mass-to-volume ratio of the hydrocarbon solvent is 1: (9 to 20) (m: v);

e、步骤d的化合物IM-1、哌啶和含氮类溶剂，于25℃～30℃搅拌反应4h～6h后，加水稀释，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到化合物IM；e, the compound IM-1 of the step d, the piperidine and the nitrogen-containing solvent are stirred at 25 ° C to 30 ° C for 4 h to 6 h, diluted with water, extracted with an ester solvent, and the organic phase is combined, and the organic phase is dried and filtered. Concentrated to obtain the compound IM;

所述化合物IM-1、哌啶与含氮类溶剂的质量体积比为1：(1～4)：(5～20)； The mass ratio of the compound IM-1, piperidine and the nitrogen-containing solvent is 1: (1 to 4): (5 to 20);

f、步骤e的化合物IM、三乙胺、

和卤烃类溶剂，于25℃～30℃搅拌反应1h～10h后，除去溶剂，得到粗品；粗品经柱层析纯化，得到化合物TM-1(a)；所述化合物IM、三乙胺、

的摩尔比为1：(1～5)：(1～2)；所述化合物IM与卤烃类溶剂的质量体积比为1：(50～100)(m：v)；f, compound IM of step e, triethylamine,

And a halogenated hydrocarbon solvent, after stirring at 25 ° C to 30 ° C for 1 h to 10 h, the solvent is removed to obtain a crude product; the crude product is purified by column chromatography to give the compound TM-1 (a); the compound IM, triethylamine,

The molar ratio is 1: (1 ~ 5): (1 ~ 2); the mass ratio of the compound IM to the halocarbon solvent is 1: (50 ~ 100) (m: v);

或者，or,

步骤e的化合物IM、三乙胺、

和卤烃类溶剂，于25℃～30℃搅拌反应1h～10h后，除去溶剂，得到粗品；粗品经柱层析纯化，得到化合物TM-1(b)；所述化合物IM、三乙胺、

的摩尔比为1：(1～5)：(1～2)；所述化合物IM与卤烃类溶剂的质量体积比为1：(50～100)(m：v)；Compound IM of step e, triethylamine,

And the halogenated hydrocarbon solvent is stirred at 25 ° C to 30 ° C for 1 h to 10 h, the solvent is removed to obtain a crude product; the crude product is purified by column chromatography to give the compound TM-1 (b); the compound IM, triethylamine,

g、0℃～5℃下，将步骤f的化合物TM-1(a)溶解于卤烃类溶剂中，加入三氟乙酸，于25℃～30℃搅拌反应1h～12h后，除去溶剂，得到粗品；粗品经制备高效液相色谱纯化，得到化合物TM(a)；所述的化合物TM-1(a)、卤烃类溶剂、三氟乙酸的质量体积比为1：(50～100)：(10～50)(m：v：v)；g, the compound TM-1 (a) of the step f is dissolved in a halogen hydrocarbon solvent at 0 ° C to 5 ° C, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C to 30 ° C for 1 h to 12 h, and then the solvent is removed. The crude product is purified by preparative high performance liquid chromatography to obtain the compound TM(a); the mass ratio of the compound TM-1 (a), the halocarbon solvent and the trifluoroacetic acid is 1: (50-100): (10~50)(m:v:v);

或者，or,

0℃～5℃下，将步骤f的化合物TM-1(b)溶解于卤烃类溶剂中，加入三氟乙酸，于25℃～30℃搅拌反应1h～12h后，除去溶剂，得到粗品；粗品经制备高效液相色谱纯化，得到化合物TM(b)；所述的化合物TM-1(b)、卤烃类溶剂、三氟乙酸的质量体积比为1：(50～100)：(10～50)(m：v：v)。The compound TM-1 (b) of the step f is dissolved in a halogen hydrocarbon solvent at 0 ° C to 5 ° C, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C to 30 ° C for 1 h to 12 h, and then the solvent is removed to obtain a crude product; The crude product is purified by preparative high performance liquid chromatography to obtain the compound TM(b); the mass ratio of the compound TM-1 (b), the halocarbon solvent and the trifluoroacetic acid is 1: (50-100): (10) ~50) (m:v:v).

优选的，包括以下步骤： Preferably, the method comprises the following steps:

a、化合物IM-4、氢氧化锂和醚类溶剂/水的混合溶剂，于25℃搅拌反应2h后，除去有机溶剂，加水稀释，调节pH＝5，析出固体，过滤，得到固体；对固体进行水洗、干燥，得到N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-甲酸；a, compound IM-4, lithium hydroxide and ether solvent / water mixed solvent, stirred at 25 ° C for 2h, the organic solvent was removed, diluted with water, adjusted to pH = 5, precipitated solid, filtered to give a solid; Washing with water and drying to obtain N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid;

所述化合物IM-4与氢氧化锂的摩尔比为1：(4.5～5)；所述化合物IM-4与混合溶剂的质量体积比为1：(10～12)(m：v)；所述混合溶剂中，醚类溶剂与水的体积比为2：1；The molar ratio of the compound IM-4 to lithium hydroxide is 1: (4.5 to 5); the mass to volume ratio of the compound IM-4 to the mixed solvent is 1: (10 to 12) (m: v); In the mixed solvent, the volume ratio of the ether solvent to water is 2:1;

b、0℃下，将步骤a的N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-甲酸溶解于卤烃类溶剂中，加入三氟乙酸，于25℃搅拌反应2h后，得到反应液；对反应液进行浓缩，得到黄色油状物，即为化合物IM-3；b, N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid of step a is dissolved in a halogen hydrocarbon solvent at 0 ° C, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C for 2 h. After that, the reaction liquid is obtained; the reaction liquid is concentrated to obtain a yellow oil, which is the compound IM-3;

所述N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-甲酸、卤烃类溶剂与三氟乙酸的质量体积比1：10：(4～5)(m：v：v)；The mass-to-volume ratio of the N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid, halocarbon solvent and trifluoroacetic acid is 1:10:(4 to 5) (m:v: v);

c、步骤b的化合物IM-3、碳酸钠、芴氧甲酰氯和醚类溶剂/水的混合溶剂，于25℃搅拌反应12h～16h后，加水稀释，调节pH＝1，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到化合物IM-2；c. The compound IM-3 of the step b, the mixed solvent of the sodium carbonate, the decyloxycarbonyl chloride and the ether solvent/water is stirred at 25 ° C for 12 h to 16 h, diluted with water, adjusted to pH=1, and extracted with an ester solvent. The organic phase is combined, the organic phase is dried, filtered, and concentrated to give the compound IM-2;

所述化合物IM-3、碳酸钠与芴氧甲酰氯的摩尔比为1：3：1；所述化合物IM-3与混合溶剂的质量体积比为1：20；所述混合溶剂中，醚类溶剂与水的体积比为5：3；The molar ratio of the compound IM-3, sodium carbonate to decanoyl chloride is 1:3:1; the mass ratio of the compound IM-3 to the mixed solvent is 1:20; in the mixed solvent, the ether The volume ratio of solvent to water is 5:3;

d、步骤c的化合物IM-2、O-(四氢-2H-吡喃-2-基)羟基胺、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、N,N-二异丙基乙胺和卤烃类溶剂，于25℃搅拌反应12h～16h后，加水稀释，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到粗品；粗品经柱层析纯化，得到化合物IM-1；d, compound IM-2 of step c, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, 2-(7-azobenzotriazole)-N,N,N',N '-Tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine and halogen hydrocarbon solvent, stirred at 25 ° C for 12h ~ 16h, diluted with water, ester solvent extraction, combined organic phase, The organic phase is dried, filtered and concentrated to give a crude product; the crude product is purified by column chromatography to give compound IM-1;

所述化合物IM-2、O-(四氢-2H-吡喃-2-基)羟基胺、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯与N,N-二异丙基乙胺的摩尔比为1：1.1：1.2：3；所述化合物IM-2与卤烃类溶剂的质量体积比为1：(9～10)(m：v)；The compound IM-2, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, 2-(7-azobenzotriazole)-N,N,N',N'-four The molar ratio of methyl urea hexafluorophosphate to N,N-diisopropylethylamine is 1:1.1:1.2:3; the mass to volume ratio of the compound IM-2 to the halocarbon solvent is 1: (9) ～10)(m:v);

e、步骤d的化合物IM-1、哌啶和含氮类溶剂，于25℃搅拌反应4h～6h后，加水稀释，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到化合物IM；e, the compound IM-1 of the step d, the piperidine and the nitrogen-containing solvent are stirred at 25 ° C for 4 h to 6 h, diluted with water, extracted with an ester solvent, and the organic phase is combined, and the organic phase is dried, filtered and concentrated. Obtaining compound IM;

所述化合物IM-1、哌啶与含氮类溶剂的质量体积比为1：2：10；The mass ratio of the compound IM-1, piperidine and nitrogen-containing solvent is 1:2:10;

f、步骤e的化合物IM、三乙胺、

和卤烃类溶剂，于25℃搅拌反应2h后，除去溶剂，得到粗品；粗品经柱层析纯化，得到化合物TM-1(a)；所述化合物IM、三乙胺、

的摩尔比为1：1.4：(1～1.2)；所述化合物IM与卤烃类溶剂的质量体积比为1：80(m：v)；f, compound IM of step e, triethylamine,

After stirring with a halocarbon solvent for 2 hours at 25 ° C, the solvent is removed to obtain a crude product; the crude product is purified by column chromatography to give the compound TM-1 (a); the compound IM, triethylamine,

The molar ratio is 1:1.4: (1 to 1.2); the mass ratio of the compound IM to the halocarbon solvent is 1:80 (m:v);

或者，or,

步骤e的化合物IM、三乙胺、

和卤烃类溶剂，于25℃搅拌反应2h后，除去溶剂，得到粗品；粗品经柱层析纯化，得到化合物TM-1(b)；所述化合物IM、三乙胺、

的摩尔比为1：1.4：(1～1.2)；所述化合物IM与卤烃类溶剂的质量体积比为1：80(m：v)；Compound IM of step e, triethylamine,

After stirring with a halocarbon solvent for 2 h at 25 ° C, the solvent is removed to obtain a crude product; the crude product is purified by column chromatography to give the compound TM-1 (b); the compound IM, triethylamine,

g、0℃下，将步骤f的化合物TM-1(a)溶解于卤烃类溶剂中，加入三氟乙酸，于25℃搅拌反应2h后，除去溶剂，得到粗品；粗品经制备高效液相色谱纯化，得到化合物TM(a)；所述的化合物TM-1(a)、卤烃类溶剂、三氟乙酸的质量体积比为1：(60～65)：25(m：v：v)；g, at 0 ° C, the compound TM-1 (a) of step f is dissolved in a halogen hydrocarbon solvent, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C for 2 h, then the solvent is removed to obtain a crude product; Purification by chromatography to obtain the compound TM (a); the mass ratio of the compound TM-1 (a), the halocarbon solvent, and the trifluoroacetic acid is 1: (60-65): 25 (m: v: v) ;

或者，or,

0℃下，将步骤f的化合物TM-1(b)溶解于卤烃类溶剂中，加入三氟乙酸，于25℃搅拌反应2h后，除去溶剂，得到粗品；粗品经制备高效液相色谱纯化，得到化合物TM(b)；所述的化合物TM-1(b)、卤烃类溶剂、三氟乙酸的质量体积比为1：(60～65)：25(m：v：v)。The compound TM-1 (b) of the step f is dissolved in a halogen hydrocarbon solvent at 0 ° C, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C for 2 h, and then the solvent is removed to obtain a crude product; the crude product is purified by preparative high performance liquid chromatography. The compound TM (b) was obtained; the mass ratio of the compound TM-1 (b), the halocarbon solvent, and the trifluoroacetic acid was 1: (60 to 65): 25 (m: v: v).

优选的，Preferably,

R₁选自氢、羟基、氰基、氟、氯、溴、羧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊烷基、己烷基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊烷氧基、己烷氧基、甲酰胺基、乙酰氨基、正丙酰胺基、异丙酰胺基、正丁酰胺基、异丁酰胺基、叔丁酰胺基、戊烷酰胺基、己烷酰胺基、甲氨酰基、乙氨酰基、正丙氨酰基、异丙氨酰基、正丁氨酰基、异丁氨酰基、叔丁氨酰基、戊氨酰基、己氨酰基、C₃的氮杂环基、C₄的氮杂环基、C₅的氮杂环基、C₆的氮杂环基、C₃的氮杂环烯基、C₄的氮杂环烯基、C₅的氮杂环烯基、C₆的氮杂环烯基或苯氧基；R _{1 is} selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentylene, hexyl Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, Acetylamino, n-propionamido, isopropylamide, n-butyryl, isobutyryl, t-butyryl, pentane amide, hexane amide, carbamoyl, acetylyl, n-alanyl , isopropylamino, n-butyryl, isobutyryl, tert-butyryl, pentyl, hexyl, aziridine of C ₃ , azacyclic of C ₄ , aza of C ₅ a cyclic group, a nitrogen heterocyclic group of C _{6 ,} a nitrogen heterocycloalkenyl group of C ₃ , azacycloheteroyl group of C ₄ , azacycloheteroyl group of C ₅ , azacycloalkenyl group of C ₆ or phenoxy group ;

R₅选自氟、氯、溴或碘；R _{5 is} selected from the group consisting of fluorine, chlorine, bromine or iodine;

m＝1或2，n＝1或2。m=1 or 2, n=1 or 2.

优选的，所述

为：Preferably, said

for:

步骤a～g中，所述醚类溶剂为四氢呋喃、***、叔丁基甲基醚、异丙醚、丁醚中的任意一种或多种；所述卤烃类溶剂为二氯甲烷、氯乙烷、二氯乙烷、三氯甲烷、四氯化碳中的任意一种或多种；所述酯类溶剂为乙酸乙酯、甲酸乙酯中的任意一种或多种；所述含氮类溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、吡啶中的任意一种或多种。In the steps a to g, the ether solvent is any one or more of tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and dibutyl ether; the halogen hydrocarbon solvent is dichloromethane or ethyl chloride. Any one or more of dichloroethane, chloroform, and carbon tetrachloride; the ester solvent is any one or more of ethyl acetate and ethyl formate; the nitrogen-containing compound The solvent is any one or more of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and pyridine.

本发明还提供了另外一种制备上述式Ⅰ所示吡咯酰胺类化合物的方法。The present invention also provides another method of preparing the pyrrole amide compound of the above formula I.

本发明提供的一种制备式Ⅰ所示吡咯酰胺类化合物的方法，它的合成路线为：The invention provides a method for preparing a pyrrole amide compound of the formula I, which has the following synthetic route:

其中，Boc代表叔丁氧羰基；TFA代表三氟乙酸；HATU代表2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；DIEA代表N,N-二异丙基乙胺；LiOH代表氢氧化锂；Wherein, Boc represents a tert-butoxycarbonyl group; TFA represents trifluoroacetic acid; and HATU represents 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DIEA stands for N,N-diisopropylethylamine; LiOH stands for lithium hydroxide;

R₅选自卤素；R _{5 is} selected from halogen;

包括以下步骤：Includes the following steps:

①、0℃～5℃下，将化合物IM-4溶解于卤烃类溶剂中，加入三氟乙酸，于20℃～30℃ 搅拌反应2h～12h，得到反应液；对反应液进行浓缩，得到黄色油状物，即为化合物IM-5；1. The compound IM-4 is dissolved in a halogen hydrocarbon solvent at 0 ° C to 5 ° C, and trifluoroacetic acid is added at 20 ° C to 30 ° C. The reaction is stirred for 2 to 12 hours to obtain a reaction liquid; the reaction liquid is concentrated to obtain a yellow oil, which is a compound IM-5;

所述IM-4、卤烃类溶剂、三氟乙酸的质量体积比1：(5～20)：(2～10)；The mass to volume ratio of the IM-4, the halocarbon solvent, and the trifluoroacetic acid is 1: (5 to 20): (2 to 10);

②、步骤①的化合物IM-5、三乙胺、

和卤烃类溶剂，于25℃～30℃搅拌反应1h～10h后；加水淬灭反应，酯类溶剂萃取，合并有机相，用饱和食盐水洗涤，对有机相进行干燥、过滤、浓缩，得到粗品；粗品经柱层析纯化，得到化合物IM-6；2. Compound IM-5, triethylamine in step 1,

And the halogenated hydrocarbon solvent is stirred at 25 ° C to 30 ° C for 1 h to 10 h; the reaction is quenched with water, the solvent is extracted, the organic phase is combined, washed with saturated brine, and the organic phase is dried, filtered and concentrated. Crude; crude product is purified by column chromatography to give compound IM-6;

所述化合物IM-5、三乙胺、

的摩尔比为1：(1～5)：(1～2)；The compound IM-5, triethylamine,

The molar ratio is 1: (1 ~ 5): (1 ~ 2);

所述化合物IM-5与卤烃类溶剂的质量体积比为1：(50～100)(m：v)；The mass to volume ratio of the compound IM-5 to the halocarbon solvent is 1: (50 to 100) (m: v);

③、步骤②的化合物IM-6、氢氧化锂和醚类溶剂/水的混合溶剂，于20℃～30℃搅拌反应10h～16h后，得到反应液；调节反应液的pH＝1～5，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到化合物IM-7；3. The compound IM-6 of the second step, a mixed solvent of lithium hydroxide and an ether solvent/water, and the reaction mixture is stirred at 20 to 30 ° C for 10 to 16 hours to obtain a reaction liquid; and the pH of the reaction solution is adjusted to 1 to 5, Extraction of the ester solvent, combining the organic phase, drying the organic phase, filtering, and concentrating to obtain the compound IM-7;

所述化合物IM-4与氢氧化锂的摩尔比为1：(1～10)；所述化合物IM-4与混合溶剂的质量体积比为1：(55～60)(m：v)；所述混合溶剂中，醚类溶剂与水的体积比为(1～5):1；The molar ratio of the compound IM-4 to lithium hydroxide is 1: (1 to 10); the mass to volume ratio of the compound IM-4 to the mixed solvent is 1: (55 to 60) (m: v); In the mixed solvent, the volume ratio of the ether solvent to water is (1 to 5): 1;

④、步骤③的化合物IM-7、1,2-二氨基苯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、N,N-二异丙基乙胺和卤烃类溶剂，于25℃～30℃搅拌反应12h～16h后，得到反应液；反应液用水稀释，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到粗品；粗品经柱层析纯化，得到化合物TM(c)；4. The compound of step 3, IM-7, 1,2-diaminobenzene, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate , N,N-diisopropylethylamine and a halogenated hydrocarbon solvent, after stirring at 25 ° C to 30 ° C for 12 h to 16 h, the reaction liquid is obtained; the reaction liquid is diluted with water, the ester solvent is extracted, and the organic phase is combined, organic The phase is dried, filtered and concentrated to obtain a crude product; the crude product is purified by column chromatography to give the compound TM(c);

所述化合物IM-7、1,2-二氨基苯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、N,N-二异丙基乙胺的摩尔比为1：(1～2)：(1～2)：(2～4)；所述化合物IM-7与卤烃类溶剂的质量体积比为1：(40～100)(m：v)。The compound IM-7, 1,2-diaminobenzene, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N, The molar ratio of N-diisopropylethylamine is 1: (1 to 2): (1 to 2): (2 to 4); the mass to volume ratio of the compound IM-7 to the halocarbon solvent is 1: (40 to 100) (m: v).

优选的，包括以下步骤：Preferably, the method comprises the following steps:

①、0℃下，将化合物IM-4溶解于卤烃类溶剂中，加入三氟乙酸，于25℃搅拌反应2h，得到反应液；对反应液进行浓缩，得到黄色油状物，即为化合物IM-5；1. At 0 ° C, the compound IM-4 was dissolved in a halogen hydrocarbon solvent, and trifluoroacetic acid was added thereto, and the reaction was stirred at 25 ° C for 2 hours to obtain a reaction liquid; the reaction liquid was concentrated to obtain a yellow oil, which was a compound IM. -5;

所述IM-4、卤烃类溶剂、三氟乙酸的质量体积比1：20：8； The mass ratio of the IM-4, the halocarbon solvent, and the trifluoroacetic acid is 1:20:8;

②、步骤①的化合物IM-5、三乙胺、

和卤烃类溶剂，于25℃搅拌反应2h后；加水淬灭反应，酯类溶剂萃取，合并有机相，用饱和食盐水洗涤，对有机相进行干燥、过滤、浓缩，得到粗品；粗品经柱层析纯化，得到化合物IM-6；2. Compound IM-5, triethylamine in step 1,

And the halogenated hydrocarbon solvent is stirred at 25 ° C for 2h; the reaction is quenched with water, the solvent is extracted, the organic phase is combined, washed with saturated brine, the organic phase is dried, filtered and concentrated to give a crude product; Purification by chromatography to give the compound IM-6;

所述化合物IM-5、三乙胺、

的摩尔比为1：(2.5～3)：(1.1～1.2)；所述化合物IM-5与卤烃类溶剂的质量体积比为1：(65～70)(m：v)；The compound IM-5, triethylamine,

The molar ratio is 1: (2.5 ~ 3): (1.1 ~ 1.2); the mass ratio of the compound IM-5 to the halocarbon solvent is 1: (65 ~ 70) (m: v);

③、步骤②的化合物IM-6、氢氧化锂和醚类溶剂/水的混合溶剂，于25℃搅拌反应12h～16h后，得到反应液；调节反应液的pH＝2，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到化合物IM-7；3. The compound IM-6 of step 2, a mixed solvent of lithium hydroxide and an ether solvent/water, and the reaction mixture is stirred at 25 ° C for 12 h to 16 h to obtain a reaction liquid; the pH of the reaction solution is adjusted to 2, and the ester solvent is extracted. The organic phase is combined, the organic phase is dried, filtered, and concentrated to give compound IM-7;

所述化合物IM-4与氢氧化锂的摩尔比为1：4.5；所述化合物IM-4与混合溶剂的质量体积比为1：(55～60)(m：v)；所述混合溶剂中，醚类溶剂与水的体积比为3:1；The molar ratio of the compound IM-4 to lithium hydroxide is 1:4.5; the mass to volume ratio of the compound IM-4 to the mixed solvent is 1:(55-60) (m:v); in the mixed solvent , the volume ratio of the ether solvent to water is 3:1;

④、步骤③的化合物IM-7、1,2-二氨基苯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、N,N-二异丙基乙胺和卤烃类溶剂，于25℃搅拌反应12h～16h后，得到反应液；反应液用水稀释，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到粗品；粗品经柱层析纯化，得到化合物TM(c)；4. The compound of step 3, IM-7, 1,2-diaminobenzene, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate , N, N-diisopropylethylamine and a halogenated hydrocarbon solvent, after stirring at 25 ° C for 12 h to 16 h, the reaction liquid is obtained; the reaction liquid is diluted with water, the ester solvent is extracted, the organic phase is combined, and the organic phase is dried. , filtration, concentration, to obtain a crude product; the crude product is purified by column chromatography to obtain the compound TM (c);

所述化合物IM-7、1,2-二氨基苯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、N,N-二异丙基乙胺的摩尔比为1：1.5：1.5：3；所述化合物IM-7与卤烃类溶剂的质量体积比为1：(40～45)(m：v)。The compound IM-7, 1,2-diaminobenzene, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N, The molar ratio of N-diisopropylethylamine is 1:1.5:1.5:3; the mass-to-volume ratio of the compound IM-7 to the halocarbon solvent is 1: (40 to 45) (m: v).

优选的，Preferably,

R₅选自氟、氯、溴或碘。R _{5 is} selected from the group consisting of fluorine, chlorine, bromine or iodine.

优选的，所述

为：Preferably, said

for:

步骤①～④中，所述卤烃类溶剂为二氯甲烷、氯乙烷、二氯乙烷、三氯甲烷、四氯化碳中的任意一种或多种；所述酯类溶剂为乙酸乙酯、甲酸乙酯中的任意一种或多种；所述醚类溶剂为四氢呋喃、***、叔丁基甲基醚、异丙醚、丁醚中的任意一种或多种。In the steps 1 to 4, the halogen hydrocarbon solvent is any one or more of dichloromethane, ethyl chloride, dichloroethane, chloroform, and carbon tetrachloride; and the ester solvent is acetic acid. Any one or more of ethyl ester and ethyl formate; the ether solvent is any one or more of tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and dibutyl ether.

上述的吡咯酰胺类化合物或其晶型、药学上可接受的盐、水合物或溶剂合物，在制备组蛋白去乙酰化酶抑制剂类药物中的用途。The use of the above-mentioned pyrrole amide compound or a crystalline form thereof, a pharmaceutically acceptable salt, a hydrate or a solvate thereof for producing a histone deacetylase inhibitor drug.

所述组蛋白去乙酰化酶抑制剂类药物是治疗由组蛋白去乙酰化酶活性异常所导致的疾病的药物。The histone deacetylase inhibitor drug is a drug for treating a disease caused by abnormal histone deacetylase activity.

进一步，所述疾病是细胞增殖疾病、自身免疫疾病、炎症、神经变性疾病或病毒性疾病中的任意一种或多种。 Further, the disease is any one or more of a cell proliferative disease, an autoimmune disease, an inflammation, a neurodegenerative disease, or a viral disease.

更进一步，所述疾病为癌症。Further, the disease is cancer.

一种抑制组蛋白去乙酰化酶活性的药物组合物，它是以上述的吡咯酰胺类化合物或其晶型、药学上可接受的盐、水合物或溶剂合物为活性成分，加上药学上常用的辅料或辅助性成分制备得到的制剂。A pharmaceutical composition for inhibiting histone deacetylase activity, which comprises the above-mentioned pyrrole amide compound or a crystalline form thereof, a pharmaceutically acceptable salt, a hydrate or a solvate thereof as an active ingredient, plus pharmacy Preparation of commonly used excipients or auxiliary ingredients.

进一步，所述的制剂包括口服给药制剂、舌下给药制剂、颊给药制剂、透皮吸收制剂或注射制剂。Further, the preparation includes an orally administered preparation, a sublingual preparation, a buccal preparation, a transdermal absorption preparation or an injection preparation.

本发明提供了一种式Ⅰ所示的新化合物，具有良好的去乙酰化酶抑制活性；同时，本发明新化合物的制备方法，具有步骤少、操作简便、安全环保、收率高等优点，非常适合产业上的应用。The invention provides a novel compound represented by the formula I, which has good deacetylase inhibitory activity; meanwhile, the preparation method of the novel compound of the invention has the advantages of fewer steps, simple operation, safety and environmental protection, high yield, etc. Suitable for industrial applications.

本发明制备得到了以下具有良好去乙酰化酶抑制活性的化合物1～19，见表1：The present invention provides the following compounds 1 to 19 having good deacetylase inhibitory activity, as shown in Table 1:

表1、本发明制备的化合物1～19Table 1. Compounds 1 to 19 prepared by the present invention

组蛋白去乙酰化酶在基因转录调控、信号转导、生长发育、分化凋亡、代谢性疾病和肿瘤等生理病理过程中发挥着重要作用。如果组蛋白去乙酰化酶活性异常，则会引发一系列组蛋白去乙酰化酶活性异常疾病。包括细胞增殖疾病、自身免疫疾病、炎症、神经变性疾病、病毒性疾病(例如，世界专利WO2011011186中HDAC6抑制剂适用的疾病综述)。Histone deacetylase plays an important role in gene transcription and regulation, signal transduction, growth and development, differentiation and apoptosis, metabolic diseases and tumors. If the histone deacetylase activity is abnormal, it will trigger a series of abnormalities in histone deacetylase activity. These include cell proliferative diseases, autoimmune diseases, inflammation, neurodegenerative diseases, viral diseases (for example, a review of diseases applicable to HDAC6 inhibitors in World Patent WO2011011186).

本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名***命名。The compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。 Definitions of terms of use in connection with the present invention: Unless otherwise stated, the initial definitions provided herein by the group or term apply to the group or term of the entire specification; for terms not specifically defined herein, it should be based on the disclosure and context. Given the meanings that those skilled in the art can give to them.

“取代”是指分子中的氢原子被其它不同的原子或分子所替换。"Substitution" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀(C a～b)烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，(C1～4)烷基是指包含1～4个碳原子的烷基。The minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix (C a to b) alkyl group indicates any alkyl group having "a" to "b" carbon atoms. Thus, for example, (C1-4) alkyl refers to an alkyl group containing from 1 to 4 carbon atoms.

术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。The term "pharmaceutically acceptable" means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form, and is physiologically Compatible with the receptor.

术语“盐”和“可药用的盐”是指上述化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。The terms "salt" and "pharmaceutically acceptable salt" refer to the above-mentioned compounds or stereoisomers thereof, acid and/or basic salts formed with inorganic and/or organic acids and bases, and also includes zwitterionic salts (within Salts) also include quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount). These salts may be precipitated in a solution and collected by filtration, or recovered after evaporation of the solvent, or may be obtained by lyophilization after reaction in an aqueous medium. The salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound. An acid salt, an oxalate salt, a malate salt, a succinate salt, a fumarate salt, a maleate salt, a tartrate salt or a trifluoroacetate salt.

本发明的某些实施方式中，本发明包括了同位素标记的化合物，所述同位素标记化合物是指与本文中所列化合物相同，但是其中的一个或多个原子被另一个原子取代，该原子的原子质量或质量数不同于自然界中常见的原子质量或质量数。可以引入式(I)化合物中的同位素包括氢、碳、氮、氧、硫，即²H,³H、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³⁵S。含有上述同位素和/或其它原子同位素的式(I)的化合物及其立体异构体，以及该化合物、立体异构体的可药用的盐均应包含在本发明范围之内。In certain embodiments of the invention, the invention includes isotopically labeled compounds, which are the same as the compounds listed herein, but wherein one or more of the atoms are replaced by another atom, the atomic The atomic mass or mass number is different from the atomic mass or mass number that is common in nature. Isotopes which may be introduced into the compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, sulfur, i.e., ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³⁵ S. Compounds of formula (I) and stereoisomers thereof containing such isotopes and/or other atomic isotopes, as well as pharmaceutically acceptable salts of such compounds, stereoisomers, are intended to be encompassed within the scope of the invention.

本发明中的关键中间体和化合物进行分离和纯化，所使用的方式是有机化学中常用的分离和纯化方法且所述方法的实例包括过滤、萃取、干燥、旋干和各种类型的色谱。可选择地，可以使中间体不经纯化即进行下一步反应。The key intermediates and compounds in the present invention are isolated and purified in a manner common to separation and purification methods in organic chemistry and examples of such methods include filtration, extraction, drying, spin drying, and various types of chromatography. Alternatively, the intermediate can be subjected to the next reaction without purification.

在某些实施方式中，本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用，用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物，则可将这些化合物同时、分别或有序地对受试对象进行给药。In certain embodiments, one or more compounds of the invention may be used in combination with one another. Alternatively, the compounds of the invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition that modulates cellular function or treats a disease. If a group of compounds is used, the compounds can be administered to the subject simultaneously, separately or sequentially.

本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorption accelerator, For example, a quaternary amine compound; (g) a wetting agent such as cetyl alcohol and glyceryl monostearate; (h) an adsorbent such as kaolin; and (i) a lubricant such as talc, calcium stearate, Magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.

固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.

除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。In addition to these inert diluents, the compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.

除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.

用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.

用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants. The active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.

本发明所述药学上可接受的辅料，是指除活性成分以外包含在剂型中的物质。The pharmaceutically acceptable excipient of the present invention means a substance which is contained in a dosage form in addition to the active ingredient.

本发明所述药学上可接受的辅助性成分，它具有一定生理活性，但该成分的加入不会改变上述药物组合物在疾病治疗过程中的主导地位，而仅仅发挥辅助功效，这些辅助功效仅仅是对该成分已知活性的利用，是医药领域惯用的辅助治疗方式。若将上述辅助性成分与本发明药物组合物配合使用，仍然应属于本发明保护的范围。The pharmaceutically acceptable auxiliary component of the present invention has certain physiological activity, but the addition of the component does not change the dominant position of the above pharmaceutical composition in the course of disease treatment, but only plays an auxiliary effect, and the auxiliary effects are only It is the utilization of the known activity of the component, and is an auxiliary treatment method conventionally used in the medical field. It is still within the scope of the present invention to use the above auxiliary ingredients in combination with the pharmaceutical composition of the present invention.

本发明所述的化合物，具有诱导分化、免疫调节、阻碍细胞周期、促进细胞凋亡的活性以及很好的HDAC亚型选择性，旨在对各种癌症具有更好的疗效，同时克服目前的HDAC抑制剂的毒副作用，如贫血、缺血性中风、深部静脉血栓形成、血小板减少和呕吐等。The compound of the present invention has the functions of inducing differentiation, immunoregulation, hindering cell cycle, promoting apoptosis, and good HDAC subtype selectivity, and aims to have better curative effect on various cancers while overcoming the current Side effects of HDAC inhibitors such as anemia, ischemic stroke, deep vein thrombosis, thrombocytopenia, and vomiting.

本发明所述的化合物具有HDAC抑制活性，可以用于治疗与HDAC活性异常相关的疾病，尤其对肝癌具有优异的效果。The compound of the present invention has HDAC inhibitory activity and can be used for treating diseases associated with abnormal HDAC activity, and particularly has excellent effects on liver cancer.

显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。Obviously, according to the above-mentioned contents of the present invention, according to the common technical knowledge and conventional means in the art, Other various modifications, substitutions or changes can be made in the form of the above-mentioned basic technical idea of the present invention.

以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Any technique implemented based on the above description of the present invention is within the scope of the present invention.

具体实施方式detailed description

本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。The raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.

实施例1 1-((4-苯甲腈)磺酰基)-N-羟基-2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 1 Preparation of 1-((4-benzonitrile)sulfonyl)-N-hydroxy-2,5-dihydro-1H-pyrrole-3-carboxamide

1、2,5-二氢-1H-吡咯-3-甲酸的制备Preparation of 1,2,5-dihydro-1H-pyrrole-3-carboxylic acid

将N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-甲酸乙酯(8.5g,36mmol；生产厂家：韶远科技(上海)有限公司)溶于60mL四氢呋喃和30mL水的混合溶液中，然后加入氢氧化锂(4.2g,176mmol)，25℃搅拌反应2小时后，真空去除有机溶剂，得到残余物；向残余物加入适量的水稀释，并用1N的盐酸调节pH＝5，析出固体，过滤，得到固体；对固体进行水洗、干燥，得到白色固体N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-甲酸(7.0g，93％收率)。Ethyl N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylate (8.5 g, 36 mmol; manufacturer: 韶远科技 (Shanghai) Co., Ltd.) was dissolved in 60 mL of tetrahydrofuran and 30 mL of water. After mixing the solution, lithium hydroxide (4.2 g, 176 mmol) was added, and the reaction was stirred at 25 ° C for 2 hours, and the organic solvent was removed in vacuo to give a residue. The residue was diluted with water and adjusted to pH = 5 with 1 N hydrochloric acid. The solid was precipitated and filtered to give a solid. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS(ESI)m/z214(M+1)⁺。MS (ESI) m / z214 ( M + 1) +.

在冰浴下，将N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-甲酸(7g,36mmol)溶于70mL二氯甲烷溶液中，然后滴加30mL三氟乙酸，搅拌，慢慢升至25℃继续搅拌反应2h，得到反应液；对反应液进行浓缩，得到黄色的油状物2,5-二氢-1H-吡咯-3-甲酸(4.0g，99％收率)。In an ice bath, N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (7 g, 36 mmol) was dissolved in 70 mL of dichloromethane, then 30 mL of trifluoroacetic acid was added dropwise and stirred. The mixture was slowly stirred to 25 ° C and the reaction was stirred for 2 h to obtain a reaction mixture. The reaction mixture was concentrated to give a yellow oil, 2,5-dihydro-1H-pyrrole-3-carboxylic acid (4.0 g, 99% yield) .

MS(ESI)m/z114(M+1)⁺。MS (ESI) m / z114 ( M + 1) +.

2、N-芴氧羰基-2,5-二氢-1H-吡咯-3-甲酸的制备2. Preparation of N-methoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid

将2,5-二氢-1H-吡咯-3-甲酸(4.0g,35.4mmol)溶于50mL的四氢呋喃和30mL的水中，然后加入碳酸钠(11.2g,106mmol)和芴氧甲酰氯(9.2g,35.4mmol；生产厂家：阿法埃莎(中国)化学有限公司)，25℃搅拌反应过夜(本发明中反应过夜是指反应时间至少为 8小时以上)；反应结束后加入200mL的水稀释，用2N的盐酸调节pH＝1，乙酸乙酯萃取，合并有机相，对有机相进行干燥、过滤、真空浓缩，得到白色固体N-芴氧羰基-2,5-二氢-1H-吡咯-3-甲酸(11.0g，92％收率)。2,5-Dihydro-1H-pyrrole-3-carboxylic acid (4.0 g, 35.4 mmol) was dissolved in 50 mL of tetrahydrofuran and 30 mL of water, then sodium carbonate (11.2 g, 106 mmol) and oxalyl chloride (9.2 g). , 35.4mmol; manufacturer: Alfa Aesar (China) Chemical Co., Ltd.), stirring reaction at 25 ° C overnight (reaction overnight in the present invention means that the reaction time is at least After more than 8 hours), after the reaction is completed, it is diluted with 200 mL of water, adjusted to pH=1 with 2N hydrochloric acid, extracted with ethyl acetate, and the organic phase is combined. The organic phase is dried, filtered and concentrated in vacuo to give a white solid N-? Carbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (11.0 g, 92% yield).

MS(ESI)m/z336(M+1)⁺。MS (ESI) m / z336 ( M + 1) +.

3、N-芴氧羰基-2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺的制备3. Preparation of N-methoxycarbonyl-2,5-dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide

将N-芴氧羰基-2,5-二氢-1H-吡咯-3-甲酸(11.0g，32.8mmol)溶于100mL的二氯甲烷中，依次加入O-(四氢-2H-吡喃-2-基)羟基胺(4.2g,36mmol)，HATU(15g,39.4mmol),DIEA(12.8g,98.4mmol；生产厂家：百灵威科技有限公司)，在25℃下搅拌反应过夜，得到反应液；向反应液中加入50mL水稀释，用乙酸乙酯萃取(50mL x 2)，合并乙酸乙酯相，对乙酸乙酯相进行干燥、过滤、浓缩，得到粗品；该粗品经过柱层析纯化，得到白色固体N-芴氧羰基-2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(12g，48％收率)。N-Methoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (11.0 g, 32.8 mmol) was dissolved in 100 mL of dichloromethane, and then O-(tetrahydro-2H-pyran- 2-yl)hydroxylamine (4.2 g, 36 mmol), HATU (15 g, 39.4 mmol), DIEA (12.8 g, 98.4 mmol; manufacturer: Belling Technology Co., Ltd.), stirring at 25 ° C overnight to obtain a reaction solution; The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (50 mL×2). The ethyl acetate phase was combined, and the ethyl acetate phase was dried, filtered and concentrated to give a crude product. White solid N-methoxycarbonyl-2,5-dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (12 g, 48% yield).

MS(ESI)m/z435(M+1)⁺。MS (ESI) m / z435 ( M + 1) +.

4、2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺的制备Preparation of 4,5,5-dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide

将N-芴氧羰基-2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(10g，23mmol)溶于100mL的DMF,然后加入20mL的哌啶，25℃搅拌反应4小时，然后加入800mL的水稀释，乙酸乙酯萃取，合并有机相；对有机相进行干燥、过滤、浓缩，得到白色固体2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(4.5g，92％收率)。N-Methoxycarbonyl-2,5-dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (10 g, 23 mmol) was dissolved in 100 mL of DMF then 20 mL of piperidine The reaction was stirred at 25 ° C for 4 hours, then diluted with 800 mL of water, extracted with ethyl acetate, and the organic phase was combined. The organic phase was dried, filtered and concentrated to give a white solid 2,5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxo)-carboxamide (4.5 g, 92% yield).

MS(ESI)m/z213(M+1)⁺。MS (ESI) m / z213 ( M + 1) +.

5、1-((4-苯甲腈)磺酰基)-N-羟基-2,5-二氢-1H-吡咯-3-甲酰胺的制备 Preparation of 1-((4-benzonitrile)sulfonyl)-N-hydroxy-2,5-dihydro-1H-pyrrole-3-carboxamide

将2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和三乙胺(66mg,0.7mmol)溶于二氯甲烷(8mL)中，25℃下，向反应液中加入4-氰基苯磺酰氯(125mg,0.5mmol；生产厂家：百灵威科技有限公司)，25℃搅拌反应2小时后，浓缩除去溶剂，得到粗品；粗品经过柱层析纯化，得到1-((4-苯甲腈)磺酰基)-N-((四氢-2H-吡喃-2-基)氧)-2,5-二氢-1H-吡咯-3-甲酰胺(80mg,39％收率)，白色固体。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and triethylamine (66 mg, 0.7 mmol) were dissolved in dichloromethane (8 mL) To the reaction mixture, 4-cyanobenzenesulfonyl chloride (125 mg, 0.5 mmol; manufacturer: Belling Technology Co., Ltd.) was added at 25 ° C, and the reaction was stirred at 25 ° C for 2 hours, and the solvent was concentrated to give a crude product; Purification by column chromatography to give 1-((4-benzonitrile)sulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)-2,5-dihydro-1H-pyrrole -3-carboxamide (80 mg, 39% yield), white solid.

在冰浴下，将1-((4-苯甲腈)磺酰基)-N-((四氢-2H-吡喃-2-基)氧)-2,5-二氢-1H-吡咯-3-甲酰胺(80mg,0.3mmol)溶于5mL二氯甲烷溶液中，然后滴加2mL三氟乙酸，搅拌，慢慢升至25℃继续搅拌反应2h，浓缩除去溶剂，得到粗品；粗品经过制备高效液相色谱纯化，得到白色固体1-((4-苯甲腈)磺酰基)-N-羟基-2,5-二氢-1H-吡咯-3-甲酰胺(13mg,25％收率)。1-((4-Benzonitrile)sulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)-2,5-dihydro-1H-pyrrole- in an ice bath 3-formamide (80 mg, 0.3 mmol) was dissolved in 5 mL of dichloromethane solution, then 2 mL of trifluoroacetic acid was added dropwise, stirred, and slowly stirred to 25 ° C. The reaction was stirred for 2 h, and the solvent was concentrated to give a crude material. Purification by high performance liquid chromatography to give 1-((4-benzonitrile)sulfonyl)-N-hydroxy-2,5-dihydro-1H-pyrrole-3-carboxamide as a white solid (13 mg, 25% yield) .

MS(ESI)m/z 294(M+1)⁺。MS (ESI) m / z 294 (M + 1) +.

1HNMR(400MHz,DMSO-d6)δ10.80(br s,1H),8.13-8.11(m,2H),8.02-8.00(m,2H),1H NMR (400MHz, DMSO-d6) δ 10.80 (br s, 1H), 8.13-8.11 (m, 2H), 8.02-8.00 (m, 2H), 6.32(s,1H),4.22-4.21(d,J＝2.4Hz,4H).6.32 (s, 1H), 4.22-4.21 (d, J = 2.4 Hz, 4H).

实施例2N-羟基-1-(苯磺酰基)-2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 2 Preparation of N-Hydroxy-1-(phenylsulfonyl)-2,5-dihydro-1H-pyrrole-3-carboxamide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和苯磺酰氯(100mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料，按照实施例1中的类似步骤制得白色固体N-羟基-1-(苯磺酰基)-2,5-二氢-1H-吡咯-3-甲酰胺(18mg,14％收率)。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and benzenesulfonyl chloride (100 mg, 0.6 mmol; manufacturer: BEHRINGER TECHNOLOGY CO., LTD. As a starting material, a white solid N-hydroxy-1-(phenylsulfonyl)-2,5-dihydro-1H-pyrrole-3-carboxamide (18 mg, 14% yield). ).

MS(ESI)m/z269(M+1)⁺。MS (ESI) m / z269 ( M + 1) +.

¹HNMR(400MHz,DMSO-d₆)δ10.80(br s,1H),9.0(br s,1H),7.84-7.82(d,J＝7.6Hz,2H),7.74-7.70(m,1H),7.66-7.62(m,2H),6.30(s,1H),4.17(s,4H)。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.80 (br s, 1H), 9.0 (br s, 1H), 7.84-7.82 (d, J = 7.6 Hz, 2H), 7.74-7.70 (m, 1H) , 7.66-7.62 (m, 2H), 6.30 (s, 1H), 4.17 (s, 4H).

实施例3N-羟基-1-((4-苯氧苯基)磺酰基)-2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 3 Preparation of N-Hydroxy-1-((4-phenoxyphenyl)sulfonyl)-2,5-dihydro-1H-pyrrole-3-carboxamide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和4-苯氧苯磺酰氯(125mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料，按照实施例1中的类似步骤制得白色固体N-羟基-1-((4-(三氟甲氧基)苯基)磺酰基)-2,5-二氢-1H-吡咯-3-甲酰胺(26mg16％收率)。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and 4-phenoxybenzenesulfonyl chloride (125 mg, 0.6 mmol; A white solid N-hydroxy-1-((4-(trifluoromethoxy)phenyl)sulfonyl)-2,5-dihydrogen was prepared according to the similar procedure in Example 1 as a starting material. -1H-pyrrole-3-carboxamide (26 mg in 16% yield).

MS(ESI)m/z361(M+1)⁺。MS (ESI) m / z361 ( M + 1) +.

¹HNMR(400MHz,DMSO-d₆)δ10.82(br s,1H),9.02(br s,1H),7.84-7.82(m,2H),7.50-7.46(m,2H),7.30-7.26(m,1H),7.18-7.12(m,4H),6.34(s,1H),4.16(s,4H)。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.82 (br s, 1H), 9.02 (br s, 1H), 7.84-7.82 (m, 2H), 7.50-7.46 (m, 2H), 7.30-7.26 ( m, 1H), 7.18-7.12 (m, 4H), 6.34 (s, 1H), 4.16 (s, 4H).

实施例4N-羟基-1-((4-乙酰胺基-3-氯苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 4 Preparation of N-Hydroxy-1-((4-acetamido-3-chlorophenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3-carboxamide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和4-乙酰胺基-3-氯苯磺酰氯(150mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料，按照实施例1中的类似步骤制得白色固体N-羟基-1-((4-乙酰胺基-3-氯苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺(47mg,10.7％收率)。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and 4-acetamido-3-chlorobenzenesulfonyl chloride (150 mg, 0.6) Methyl acetate N-hydroxy-1-((4-acetamido-3-chlorophenyl)sulfonyl) 2 was obtained as a starting material in the same manner as in Example 1. 5-Dihydro-1H-pyrrole-3-carboxamide (47 mg, 10.7% yield).

MS(ESI)m/z360(M+1)⁺。MS (ESI) m / z360 ( M + 1) +.

¹HNMR(400MHz,CD₃OD)δ8.25-8.23(d,J＝8.8Hz,1H),7.74(d,J＝0.8Hz，1H),7.80-7.78(m,1H),6.38(s,1H),4.28(s,4H),2.25(s,3H)。 ¹ H NMR (400 MHz, CD ₃ OD) δ 8.25-8.23 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 0.8 Hz, 1H), 7.80-7.78 (m, 1H), 6.38 (s, 1H), 4.28 (s, 4H), 2.25 (s, 3H).

实施例5N-羟基-1-((2,3-二氢苯并[b][1,4]二恶英)-6-磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺的制备 Example 5 N-Hydroxy-1-((2,3-dihydrobenzo[b][1,4]dioxin)-6-sulfonyl)2,5-dihydro-1H-pyrrole-3-A Preparation of amide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和2,3-二氢苯并[b][1,4]二恶英-6-磺酰氯(132mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料，按照实施例1中的类似步骤制得白色固体N-羟基-1-((2,3-二氢苯并[b][1,4]二恶英)-6-磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺(12mg,8.0％收率)。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and 2,3-dihydrobenzo[b][1,4] Dioxin-6-sulfonyl chloride (132 mg, 0.6 mmol; manufacturer: Belling Technology Co., Ltd.) was used as a raw material, and a white solid N-hydroxy-1-((2,3-di) was obtained according to the similar procedure in Example 1. Hydrobenzo[b][1,4]dioxin)-6-sulfonyl) 2,5-dihydro-1H-pyrrole-3-carboxamide (12 mg, 8.0% yield).

MS(ESI)m/z327(M+1)⁺。MS (ESI) m / z327 ( M + 1) +.

¹HNMR(400MHz,DMSO-d₆)δ10.80(s,1H),9.05(br s,1H),7.31-7.26(m,2H),7.09-7.07(d,J＝8.4Hz,1H),6.32(s,1H),4.34-4.31(m,4H),4.14(s,4H)。 ^{1 HNMR (400MHz, DMSO-d} 6) δ10.80 (s, 1H), 9.05 (br s, 1H), 7.31-7.26 (m, 2H), 7.09-7.07 (d, J = 8.4Hz, 1H), 6.32 (s, 1H), 4.34 - 4.31 (m, 4H), 4.14 (s, 4H).

实施例6N-羟基-1-((2,3-苯并二氢呋喃)-6-磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 6 Preparation of N-Hydroxy-1-((2,3-benzodihydrofuran)-6-sulfonyl) 2,5-dihydro-1H-pyrrole-3-carboxamide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和2,3-苯并二氢呋喃-6-磺酰氯(123mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料，按照实施例1中的类似步骤制得白色固体N-羟基-1-((2,3-苯并二氢呋喃)-6-磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺(10mg,6.8％收率)。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and 2,3-benzodihydrofuran-6-sulfonyl chloride (123 mg) , 0.6 mmol; manufacturer: Belling Technology Co., Ltd.) as a raw material, according to the similar procedure in Example 1 to obtain a white solid N-hydroxy-1-((2,3-benzodihydrofuran)-6-sulfonyl 2,5-Dihydro-1H-pyrrole-3-carboxamide (10 mg, 6.8% yield).

MS(ESI)m/z311(M+1)⁺。MS (ESI) m / z311 ( M + 1) +.

¹HNMR(400MHz,DMSO-d₆)δ10.82(s,1H),9.05(br s,1H),7.69(d,J＝1.6Hz,1H),7.59-7.57(m,1H),6.96-6.94(d,J＝8.4Hz,1H),6.31(s,1H),4.67-4.62(t,J＝8.8Hz,2H),4.13(s,4H),3.29-3.24(t,J＝8.8Hz,2H)。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.82 (s, 1H), 9.05 (br s, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.59-7.57 (m, 1H), 6.96- 6.94 (d, J = 8.4 Hz, 1H), 6.31 (s, 1H), 4.67-4.62 (t, J = 8.8 Hz, 2H), 4.13 (s, 4H), 3.29-3.24 (t, J = 8.8 Hz) , 2H).

实施例7N-羟基-1-((4-甲酸基)-苯磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 7 Preparation of N-Hydroxy-1-((4-carboxy)-benzenesulfonyl) 2,5-dihydro-1H-pyrrole-3-carboxamide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和4-(氯磺酰基)苯甲酸(124mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料，按照实施例1中的类似步骤制得白色固体N-羟基-1-((4-甲酸基)-苯磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺(116mg,79％收率)。Production of 2,5-dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and 4-(chlorosulfonyl)benzoic acid (124 mg, 0.6 mmol; The manufacturer: Bailingwei Technology Co., Ltd.) as a raw material, according to the similar procedure in Example 1, a white solid N-hydroxy-1-((4-carboxylic acid)-benzenesulfonyl) 2,5-dihydro-1H-pyrrole was obtained. -3-carboxamide (116 mg, 79% yield).

MS(ESI)m/z 313(M+1)⁺。MS (ESI) m / z 313 (M + 1) +.

¹HNMR(400MHz,DMSO-d₆)δ10.81(br s,1H),9.05(br s,1H),8.16-8.14(d,J＝8.4Hz,2H),7.96-7.94(d,J＝8.4Hz,3H),6.32(s,1H),4.40(s,4H)。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.81 (br s, 1H), 9.05 (br s, 1H), 8.16-8.14 (d, J = 8.4 Hz, 2H), 7.96-7.94 (d, J = 8.4 Hz, 3H), 6.32 (s, 1H), 4.40 (s, 4H).

实施例8N-羟基-1-((4-(叔丁基)苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 8 Preparation of N-Hydroxy-1-((4-(tert-butyl)phenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3-carboxamide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和4-(叔丁基)苯基)磺酰氯(130mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料,按照实施例1中的类似步骤制得白色固体N-羟基-1-((4-(叔丁基)苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺(10mg,6％收率)。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and 4-(tert-butyl)phenyl)sulfonyl chloride (130 mg, 0.6) Methyl; N-hydroxy-1-((4-(tert-butyl)phenyl)sulfonyl) 2,5-, as a starting material, according to a similar procedure as in Example 1. Dihydro-1H-pyrrole-3-carboxamide (10 mg, 6% yield).

MS(ESI)m/z 325(M+1)⁺。MS (ESI) m / z 325 (M + 1) +.

¹HNMR(400Hz,CD₃OD)δ7.81-7.79(m,2H),7.69-7.67(m,2H),6.36(s,1H),4.26(s,4H),1.37(s,9H)。 ¹ H NMR (400 Hz, CD ₃ OD) δ 7.81-7.79 (m, 2H), 7.69-7.67 (m, 2H), 6.36 (s, 1H), 4.26 (s, 4H), 1.37 (s, 9H).

实施例9N-羟基-1-((4-(甲胺羰基)苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 9 Preparation of N-Hydroxy-1-((4-(methylaminocarbonyl)phenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3-carboxamide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和4-(甲胺羰基)苯磺酰氯(128mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料，按照实施例1中的类似步骤制得白色固体N-羟基-1-((4-(甲胺羰基)苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺(25mg,16％收率)。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and 4-(methylaminocarbonyl)benzenesulfonyl chloride (128 mg, 0.6 mmol; The manufacturer: Belling Technology Co., Ltd.) as a raw material, according to the similar procedure in Example 1, a white solid N-hydroxy-1-((4-(methylaminocarbonyl)phenyl)sulfonyl) 2,5-dihydrogen was obtained. -1H-pyrrole-3-carboxamide (25 mg, 16% yield).

MS(ESI)m/z 326(M+1)⁺。MS (ESI) m / z 326 (M + 1) +.

¹HNMR(400MHz,DMSO-d₆)δ11.81(br s,1H),9.05(br s,1H),8.67(br s,1H),8.04-8.02 (d,J＝8.4Hz,2H),7.93-7.91(d,J＝8.4Hz,3H),6.32(s,1H),4.20(s,4H)。 ^{1 HNMR (400MHz, DMSO-d} 6) δ11.81 (br s, 1H), 9.05 (br s, 1H), 8.67 (br s, 1H), 8.04-8.02 (d, J = 8.4Hz, 2H), 7.93-7.91 (d, J = 8.4 Hz, 3H), 6.32 (s, 1H), 4.20 (s, 4H).

实施例10N-羟基-1-((4-乙酰胺基苯)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 10 Preparation of N-Hydroxy-1-((4-acetamidophenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3-carboxamide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和4-(乙酰胺基)苯磺酰氯(128mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料，按照实施例1中的类似步骤制得白色固体N-羟基-1-((4-乙酰胺基苯)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺(15mg,9.6％收率)。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and 4-(acetamido)benzenesulfonyl chloride (128 mg, 0.6 mmol; The manufacturer: Belling Technology Co., Ltd.) as a raw material, according to the similar procedure in Example 1, a white solid N-hydroxy-1-((4-acetamidophenyl)sulfonyl) 2,5-dihydro-1H- Pyrrole-3-carboxamide (15 mg, 9.6% yield).

MS(ESI)m/z 326(M+1)⁺。MS (ESI) m / z 326 (M + 1) +.

¹HNMR(400MHz,CD3OD)δ7.82(s,4H),6.38(s,1H),4.25(s,4H),2.17(s,3H)。 ¹ H NMR (400 MHz, CD3 OD) δ 7.82 (s, 4H), 6.38 (s, 1H), 4.25 (s, 4H), 2.17 (s, 3H).

实施例11N-羟基-1-((4-氟苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 11 Preparation of N-Hydroxy-1-((4-fluorophenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3-carboxamide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和4-氟苯磺酰氯(109mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料,按照实施例1中的类似步骤制得白色固体N-羟基-1-((4-氟苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺(33mg,25％收率)。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and 4-fluorobenzenesulfonyl chloride (109 mg, 0.6 mmol; As a raw material, according to the similar procedure in Example 1, a white solid N-hydroxy-1-((4-fluorophenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3-A was obtained. Amide (33 mg, 25% yield).

MS(ESI)m/z 287(M+1)⁺。MS (ESI) m / z 287 (M + 1) +.

¹HNMR(400Hz,CD3OD)δ7.96-7.93(dd,J＝4.8，8.0Hz,2H),7.39-7.35(m,2H),6.4(s,1H),4.3(s,4H)。 ¹ H NMR (400 Hz, CD 3 OD) δ 7.96-7.93 (dd, J = 4.8, 8.0 Hz, 2H), 7.39-7.35 (m, 2H), 6.4 (s, 1H), 4.3 (s, 4H).

实施例12N-羟基-1-((3-氟苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 12 Preparation of N-Hydroxy-1-((3-fluorophenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3-carboxamide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和3-氟苯磺酰氯(109mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料,按照实施例1中的类似步骤制得白色固体N-羟基-1-((3-氟苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺(33mg,25％收率)。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and 3-fluorobenzenesulfonyl chloride (109 mg, 0.6 mmol; As a raw material, according to the similar procedure in Example 1, a white solid N-hydroxy-1-((3-fluorophenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3-A was obtained. Amide (33 mg, 25% yield).

MS(ESI)m/z 287(M+1)⁺。MS (ESI) m / z 287 (M + 1) +.

¹HNMR(400Hz,CD3OD)δ＝8.17-8.12(m,J＝8.0Hz,2H),8.03-8.01(d,1H),7.89-7.85(m,1H),6.38(s,1H),4.31(s,4H)。 ¹ H NMR (400 Hz, CD 3 OD) δ = 8.17 - 8.12 (m, J = 8.0 Hz, 2H), 8.03 - 8.01 (d, 1H), 7.89 - 7.85 (m, 1H), 6.38 (s, 1H), 4.31 ( s, 4H).

实施例13N-羟基-1-((4-甲氧苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 13 Preparation of N-Hydroxy-1-((4-methoxyphenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3-carboxamide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和4-甲氧基苯磺酰氯(123mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料,按照实施例1中的类似步骤制得白色固体N-羟基-1-((4-甲氧苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺(34mg,23％收率)。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and 4-methoxybenzenesulfonyl chloride (123 mg, 0.6 mmol; manufacturer :Belling Technology Co., Ltd. as a raw material, according to the similar procedure in Example 1, a white solid N-hydroxy-1-((4-methoxyphenyl)sulfonyl) 2,5-dihydro-1H-pyrrole- 3-formamide (34 mg, 23% yield).

MS(ESI)m/z 299(M+1)⁺。MS (ESI) m / z 299 (M + 1) +.

¹HNMR(400Hz,CD3OD)δ＝7.828-7.805(d,J＝8Hz,2H),7.145-7.123(d,J＝8.8Hz,2H),6.432(s,1H),4.242(s,4H),3.896(s,3H)。 ¹ H NMR (400 Hz, CD 3 OD) δ = 7.828-7.805 (d, J = 8 Hz, 2H), 7.145-7.123 (d, J = 8.8 Hz, 2H), 6.432 (s, 1H), 4.242 (s, 4H), 3.896 (s, 3H).

实施例14N-羟基-1-((3-甲氧苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 14 Preparation of N-Hydroxy-1-((3-methoxyphenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3-carboxamide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和3-甲氧基苯磺酰氯(123mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料,按照实施例1中的类似步骤制得白色固体N-羟基-1-((3-甲氧苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺(36mg,24％收率)。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and 3-methoxybenzenesulfonyl chloride (123 mg, 0.6 mmol; manufacturer :Belling Technology Co., Ltd. as a raw material, according to the similar procedure in Example 1, a white solid N-hydroxy-1-((3-methoxyphenyl)sulfonyl) 2,5-dihydro-1H-pyrrole- 3-formamide (36 mg, 24% yield).

LC-MS(ESI)m/z 299(M+H)⁺。LC-MS (ESI) m / z 299 (M + H) +.

¹HNMR(400Hz,DMSO-D₆)δ＝10.80(s,1H),9.02(s,1H),7.59-7.55(m,1H),7.41-7.39(d,J＝8Hz,1H),7.30-7.27(m,2H),6.35(s,1H),4.19(s,4H),3.85(s,3H)。 ¹ H NMR (400 Hz, DMSO-D ₆ ) δ = 10.80 (s, 1H), 9.02 (s, 1H), 7.59-7.55 (m, 1H), 7.41 - 7.39 (d, J = 8 Hz, 1H), 7.30- 7.27 (m, 2H), 6.35 (s, 1H), 4.19 (s, 4H), 3.85 (s, 3H).

实施例15N-羟基-1-((4-甲基苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺的制备 Example 15 Preparation of N-Hydroxy-1-((4-methylphenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3-carboxamide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和4-甲基苯磺酰氯(114mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料,按照实施例1中的类似步骤制得白色固体N-羟基-1-((4-甲基苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺(26mg,19％收率)。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and 4-methylbenzenesulfonyl chloride (114 mg, 0.6 mmol; The white solid N-hydroxy-1-((4-methylphenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3 was prepared according to the similar procedure in Example 1 as a starting material. - Formamide (26 mg, 19% yield).

MS(ESI)m/z 283(M+1)⁺。MS (ESI) m / z 283 (M + 1) +.

¹HNMR(400MHz,CD₃OD)δ＝7.76(d,J＝8.4Hz,2H),7.44(d,J＝8.0Hz,2H),6.35(s,1H),4.25(s,4H),2.45(s,3H)。 ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.76 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 6.35 (s, 1H), 4.25 (s, 4H), 2.45 (s, 3H).

实施例16N-羟基-1-((3-甲基苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 16 Preparation of N-Hydroxy-1-((3-methylphenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3-carboxamide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和3-甲基苯磺酰氯(114mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料,按照实施例1中的类似步骤制得白色固体N-羟基-1-((3-甲基苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺(24mg,18％收率)。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and 3-methylbenzenesulfonyl chloride (114 mg, 0.6 mmol; Whitening solid N-hydroxy-1-((3-methylphenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3 was prepared according to the similar procedure of Example 1 as a starting material. - Formamide (24 mg, 18% yield).

MS(ESI)m/z 283(M+1)⁺。MS (ESI) m / z 283 (M + 1) +.

¹HNMR(400MHz,CD₃OD)δ＝7.70～7.66(m,2H),7.52～7.51(m,2H),6.36(s,1H),4.26(s,4H),2.46(s,3H)。 ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.70 - 7.66 (m, 2H), 7.52 - 7.51 (m, 2H), 6.36 (s, 1H), 4.26 (s, 4H), 2.46 (s, 3H).

实施例17N-羟基-1-((3，4-二甲氧苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 17 Preparation of N-Hydroxy-1-((3,4-dimethoxyphenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3-carboxamide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和3,4-二甲氧基苯磺酰氯(114mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料,按照实施例1中的类似步骤制得白色固体N-羟基-1-((3，4-二甲氧苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺(24mg, 18％收率)。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and 3,4-dimethoxybenzenesulfonyl chloride (114 mg, 0.6 mmol) ;Manufacturer:Belling Technology Co., Ltd.) as a raw material, according to the similar procedure in Example 1, a white solid N-hydroxy-1-((3,4-dimethoxyphenyl)sulfonyl) 2,5-di Hydrogen-1H-pyrrole-3-carboxamide (24mg, 18% yield).

MS(ESI)m/z 329(M+1)⁺。MS (ESI) m / z 329 (M + 1) +.

¹HNMR(400Hz,DMSO-D₆)δ＝10.80(s,1H),9.13(s,1H),7.50-7.48(m,1H),7.31-7.24(m,2H),6.38(s,1H),4.24(s,4H),3.92(s,3H)。 ¹ H NMR (400 Hz, DMSO-D ₆ ) δ=10.80 (s, 1H), 9.13 (s, 1H), 7.50-7.48 (m, 1H), 7.31-7.24 (m, 2H), 6.38 (s, 1H) , 4.24 (s, 4H), 3.92 (s, 3H).

实施例18N-羟基-1-((4-(1,2,36-四氢吡啶-4-基)苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 18 Preparation of N-Hydroxy-1-((4-(1,2,36-tetrahydropyridin-4-yl)phenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3-carboxamide

以2,5-二氢-1H-吡咯-3-(四氢吡喃-2-氧)-甲酰胺(100mg,0.5mmol)和4-(1,2,36-四氢吡啶-4-基)苯基)磺酰氯(114mg,0.6mmol；生产厂家：百灵威科技有限公司)为原料，按照实施例1中的类似步骤制得白色固体N-羟基-1-((4-(1,2,36-四氢吡啶-4-基)苯基)磺酰基)2,5-二氢-1H-吡咯-3-甲酰胺(26mg,15％收率)。2,5-Dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100 mg, 0.5 mmol) and 4-(1,2,36-tetrahydropyridin-4-yl Phenyl)sulfonyl chloride (114 mg, 0.6 mmol; manufacturer: Belling Technology Co., Ltd.) was used as a starting material, and a white solid N-hydroxy-1-((4-(1,2, 36-tetrahydropyridin-4-yl)phenyl)sulfonyl) 2,5-dihydro-1H-pyrrole-3-carboxamide (26 mg, 15% yield).

MS(ESI)m/z 350(M+1)⁺。MS (ESI) m / z 350 (M + 1) +.

实施例19N-(2-氨基苯基)-1-(苯磺酰基)-2,5-二氢-1H-吡咯-3-甲酰胺的制备Example 19 Preparation of N-(2-Aminophenyl)-1-(phenylsulfonyl)-2,5-dihydro-1H-pyrrole-3-carboxamide

1、2,5-二氢-1H-吡咯-3-甲酸乙酯的制备Preparation of 1,2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester

在冰浴下，将N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-甲酸乙酯(250mg,1.1mmol)溶于5mL二氯甲烷溶液中，然后滴加2mL三氟乙酸，搅拌，慢慢升至25℃继续搅拌反应2h，得到反应液；然后对反应液进行浓缩，得到黄色的油状化合物2,5-二氢-1H-吡咯-3-甲酸乙酯(150mg，99％收率)。Ethyl N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylate (250 mg, 1.1 mmol) was dissolved in 5 mL of dichloromethane under ice bath, then 2 mL of trifluorohexane was added dropwise. Acetic acid, stirring, and slowly increasing to 25 ° C, the reaction was stirred for 2 h to obtain a reaction liquid; then the reaction mixture was concentrated to give a yellow oily compound 2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester (150 mg, 99% yield).

MS(ESI)m/z 142(M+1)+。MS (ESI) m/z 142 (M+1).

2、1-苯基磺酰基-2,5-二氢-1H-吡咯-3-甲酸乙酯的制备 2. Preparation of ethyl 1-phenylsulfonyl-2,5-dihydro-1H-pyrrole-3-carboxylate

在冰浴下，向2,5-二氢-1H-吡咯-3-甲酸乙酯(150mg,1.1mmol)和三乙胺(310mg,3.1mmol)的二氯甲烷(10mL)溶液中慢慢加入苯磺酰氯(222mg,1.3mmol)，缓慢升至25℃后再继续搅拌反应2个小时后，加入10mL水淬灭反应，得到反应液；用乙酸乙酯萃取(50mLx 2)，合并有机相，用饱和食盐水洗(10mLx 2)，对有机相进行干燥、过滤、浓缩后，得到粗品；粗品经柱层析(硅胶，石油醚:乙酸乙酯＝6:1)纯化，得到化合物1-苯基磺酰基-2,5-二氢-1H-吡咯-3-甲酸乙酯(280mg,94％收率)，白色固体。Slowly added to a solution of 2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester (150 mg, 1.1 mmol) and triethylamine (310 mg, 3.1 mmol) in dichloromethane (10 mL) The benzenesulfonyl chloride (222 mg, 1.3 mmol) was slowly warmed to 25 ° C, and the reaction was further stirred for 2 hours. Then, the reaction mixture was quenched with 10 mL of water to give a reaction mixture, which was extracted with ethyl acetate (50 mL×2). The organic phase was dried (MgSO4, EtOAc (EtOAc:EtOAc) Ethyl sulfonyl-2,5-dihydro-1H-pyrrole-3-carboxylate (280 mg, 94% yield), white solid.

MS(ESI)m/z 281(M+1)+。MS (ESI) m/z 281 (M+1).

3、1-苯基磺酰基-2,5-二氢-1H-吡咯-3-甲酸的制备3. Preparation of 1-phenylsulfonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid

在25℃下，将LiOH(179mg,4.5mmol)加入1-苯基磺酰基-2,5-二氢-1H-吡咯-3-甲酸乙酯(280mg,1.0mmol)的四氢呋喃(12mL)和水(4mL)溶液中并搅拌过夜，得到反应液；然后在冰浴下用1N的盐酸调节反应液pH＝2，再以乙酸乙酯萃取(10mL x 3)，合并有机相；对有机相进行干燥、过滤、浓缩，得到1-苯基磺酰基-2,5-二氢-1H-吡咯-3-甲酸(223mg，64％收率)，所得产品不需要进一步纯化，直接用于下一步反应。Add LiOH (179 mg, 4.5 mmol) to ethyl 1-phenylsulfonyl-2,5-dihydro-1H-pyrrole-3-carboxylate (280 mg, 1.0 mmol) in tetrahydrofuran (12 mL) and water at 25 ° C (4 mL) and stirred overnight to obtain a reaction mixture; then, the reaction mixture was adjusted to pH 2 with 1N hydrochloric acid, and then extracted with ethyl acetate (10 mL x 3), and the organic phase was combined; Filtration and concentration gave 1-phenylsulfonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (223 mg, yield: 64%).

MS(ESI)m/z 267(M+1)+。MS (ESI) m/z 266 (M+1).

4、N-(2-氨基苯基)-1-(苯磺酰基)-2,5-二氢-1H-吡咯-3-甲酰胺的制备4. Preparation of N-(2-aminophenyl)-1-(phenylsulfonyl)-2,5-dihydro-1H-pyrrole-3-carboxamide

将1-苯基磺酰基-2,5-二氢-1H-吡咯-3-甲酸(223mg，0.6mmol)溶于10mL的二氯甲烷中，溶液中依次加入1,2-二氨基苯(104mg,0.9mmol)，HATU(338mg,0.9mmol),DIEA(229mg,1.8mmol)，在25℃下搅拌反应过夜，得到反应液；反应液用20mL水稀释，乙酸乙酯萃取(50mL x 2)，合并有机相；对有机相进行干燥、过滤、浓缩，得到粗品；粗品经过制备高效液相色谱纯化，得到N-(2-氨基苯基)-1-(苯磺酰基)-2,5-二氢-1H-吡咯-3-甲酰胺(52mg,22％收率)。1-Phenylsulfonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (223 mg, 0.6 mmol) was dissolved in 10 mL of dichloromethane, and then 1,2-diaminobenzene (104 mg) was added to the solution. , 0.9 mmol), HATU (338 mg, 0.9 mmol), DIEA (229 mg, 1.8 mmol), stirred at 25 ° C overnight to give a reaction mixture; the reaction solution was diluted with 20 mL of water, B Ethyl acetate extraction (50 mL x 2), the organic phase is combined; the organic phase is dried, filtered, and concentrated to give a crude material. The crude product is purified by preparative high-performance liquid chromatography to give N-(2-aminophenyl)-1-( Benzenesulfonyl)-2,5-dihydro-1H-pyrrole-3-carboxamide (52 mg, 22% yield).

MS(ESI)m/z 344(M+1)+。MS (ESI) m/z 344 (M+1).

¹HNMR(400MHz,CD3OD)δ9.5(br s,1H),7.9-7.8(m,2H),7.7-7.6(m,3H),7.1-7.0(m,4H),6.7(s,1H),4.3(s,4H)。 ¹ H NMR (400 MHz, CD 3 OD) δ 9.5 (br s, 1H), 7.9-7.8 (m, 2H), 7.7-7.6 (m, 3H), 7.1-7.0 (m, 4H), 6.7 (s, 1H) , 4.3 (s, 4H).

为了说明本发明的有益效果，本发明提供以下试验例：In order to illustrate the beneficial effects of the present invention, the present invention provides the following test examples:

试验例1生物学活性检测Test Example 1 Biological Activity Test

在底物去乙酰化检测中对本发明化合物的HDA抑制活性进行检测。The HDA inhibitory activity of the compounds of the invention is tested in a substrate deacetylation assay.

A：去乙酰化酶6的酶活性检测(#50076，BPS Bioscience)：A: Detection of enzymatic activity of deacetylase 6 (#50076, BPS Bioscience):

HDAC 6脱去底物上的乙酰基，使得底物活化，能够被后续加入的显色液作用并释放荧光基团，其荧光信号的大小反映了HDAC 6的活力。该酶的IC50检测方法在Chuping Xu,Elisabetta Soragni Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurdegenerative DiseaseFriedreich’s Ataxia:A New Synthetic Route中公开。总反应体系中(100μL/well)含0.35ng/μL的HDAC 6，20μM底物及不同浓度的化合物。37℃孵育30分钟后测定其荧光信号，从所得数据确定化合物的抑制作用并将其与化合物浓度作图，得到浓度响应曲线，按照四参数模型拟合IC50值。HDAC 6 removes the acetyl group on the substrate, allowing the substrate to activate, being able to act on the subsequently added chromogenic solution and releasing the fluorophore, the magnitude of which reflects the activity of HDAC 6. The IC50 detection method for this enzyme is disclosed in Chuping Xu, Elisabetta Soragni Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurdegenerative Disease Friedreich's Ataxia: A New Synthetic Route. The total reaction system (100 μL/well) contained 0.35 ng/μL of HDAC 6, 20 μM substrate and various concentrations of compound. After incubating at 37 ° C for 30 minutes, the fluorescence signal was measured, and the inhibition of the compound was determined from the obtained data and plotted against the compound concentration to obtain a concentration response curve, and the IC50 value was fitted according to a four-parameter model.

B：去乙酰化酶3酶活性检测(#50003，BPS Bioscience)：B: Deacetylase 3 enzyme activity assay (#50003, BPS Bioscience):

HDAC 3脱去底物上的乙酰基，使得底物活化，能够被显色液作用并释放荧光基团，其荧光信号的大小反映了HDAC 3的活力。该酶的IC50检测方法在Chuping Xu,Elisabetta Soragni Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurdegenerative DiseaseFriedreich’s Ataxia:A New Synthetic Route中公开。总反应体系中(100μL/well)含0.16ng/μL的HDAC 3,10μM底物及不同浓度的化合物。于Ex/Em＝360/460在线检测荧光信号。从所得数据确定化合物的抑制作用并将其与化合物浓度作图，得到浓度响应曲线，按照四参数模型拟合IC50值。HDAC 3 removes the acetyl group on the substrate, activates the substrate, acts on the chromogenic solution and releases the fluorophore, and the size of the fluorescent signal reflects the activity of HDAC 3. The IC50 detection method for this enzyme is disclosed in Chuping Xu, Elisabetta Soragni Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurdegenerative Disease Friedreich's Ataxia: A New Synthetic Route. The total reaction system (100 μL/well) contained 0.16 ng/μL of HDAC 3, 10 μM substrate and various concentrations of compounds. Fluorescence signals were detected online at Ex/Em=360/460. The inhibition of the compound was determined from the obtained data and plotted against the compound concentration to obtain a concentration response curve, and the IC50 value was fitted according to a four-parameter model.

按照上述方法对实施例制备的化合物1～19进行去乙酰化酶6(即HDAC6)的酶活性检测，试验结果见表2，其中测定各化合物的IC50按照说明分类，表2中：The enzymatic activities of deacetylase 6 (i.e., HDAC6) were tested for the compounds 1 to 19 prepared in the examples according to the above methods. The test results are shown in Table 2, wherein the IC50 of each compound was determined according to the description, in Table 2:

“+”表示HDAC6的IC50测定大于500nM；"+" indicates that the IC50 of HDAC6 is determined to be greater than 500 nM;

“++”表示HDAC6的IC50小于300nM大于100nM；"++" means that the IC50 of HDAC6 is less than 300nM greater than 100nM;

“+++”表示HDAC6的IC50小于100nM“+++” means that the IC50 of HDAC6 is less than 100nM

按照上述方法对实施例制备的化合物1～19进行去乙酰化酶3(即HDAC3)的酶活性检测，试验结果见表2，其中测定各化合物的IC50按照说明分类，表2中：The enzymatic activities of deacetylase 3 (i.e., HDAC3) of the compounds 1 to 19 prepared in the examples were tested according to the above methods. The test results are shown in Table 2, wherein the IC50 of each compound was determined according to the description, in Table 2:

“+”表示HDAC3的IC50测定大于1000nM； "+" indicates that the IC50 of HDAC3 is determined to be greater than 1000 nM;

“++”表示HDAC3的IC50大于100nM小于1000nM；"++" means that the IC50 of HDAC3 is greater than 100nM and less than 1000nM;

“+++”表示HDAC3的IC50小于100nM。"+++" means that the IC50 of HDAC3 is less than 100nM.

表2、化合物对HDAC6&HDAC3的抑制活性Table 2. Inhibitory activity of compounds on HDAC6 & HDAC3

化合物Compound	活性(HDAC6)Activity (HDAC6)	活性(HDAC3)Activity (HDAC3)	化合物Compound	活性(HDAC6)Activity (HDAC6)	活性(HDAC3)Activity (HDAC3)
11	++++	N.D.N.D.	1111	++++++	N.D.N.D.
22	++++++	++	1212	++++++	N.D.N.D.
33	++++	++++	1313	++++++	N.D.N.D.
44	++++++	++++	1414	++++++	N.D.N.D.
55	++++++	++	1515	++++++	N.D.N.D.
66	++++++	++++	1616	++++++	N.D.N.D.
77	++++++	N.D.N.D.	1717	++++	N.D.N.D.
88	++++++	++++	1818	++++	N.D.N.D.
99	++++++	N.D.N.D.	1919	++	N.D.N.D.
1010	++++++	N.D.N.D.

ND:数据正在检测分析中。ND: Data is being analyzed and analyzed.

试验表明，本发明化合物1～19具有良好的去乙酰化酶抑制活性，可以有效用于与组蛋白去乙酰化酶活性异常疾病的治疗。Tests have shown that the compounds 1 to 19 of the present invention have good deacetylase inhibitory activity and can be effectively used for the treatment of diseases in which the histone deacetylase activity is abnormal.

试验例2细胞测定–细胞生长抑制测定Test Example 2 Cell assay - Cell growth inhibition assay

材料和试剂Materials and reagents

HepG2细胞株、Hep3B细胞株、Huh7细胞株、Li7细胞株均购自中国科学院上海生命科学研究院；DMEM高糖培养基和MEM培养基购自Hyclone；胎牛血清购自Gibco公司；胰蛋白酶购自Invitrogen Shanghai；CCK-8试剂盒购自碧云天生物技术研究所(beyotime)；其余细胞培养皿等耗材均购自康宁中国公司(Corning China)。HepG2 cell line, Hep3B cell line, Huh7 cell line and Li7 cell line were purchased from Shanghai Institute of Biological Sciences, Chinese Academy of Sciences; DMEM high glucose medium and MEM medium were purchased from Hyclone; fetal bovine serum was purchased from Gibco; trypsin was purchased. From Invitrogen Shanghai; CCK-8 kit was purchased from Biyuntian Biotechnology Research Institute (beyotime); other cell culture dishes and other consumables were purchased from Corning China.

化合物作用前的细胞准备Cell preparation before compound action

用胰蛋白酶消化对数生长期的HepG2细胞、Hep3B细胞、Huh7细胞、Li7细胞，取均匀细胞悬液计数后以含10％血清的培养基调整细胞密度为1500个细胞/孔，重新接种于96孔细胞培养板中，培养体积200μL，于37℃，5％CO₂培养箱培养；培养24小时即可用于实验。 HepG2 cells, Hep3B cells, Huh7 cells and Li7 cells in the logarithmic growth phase were digested with trypsin, and the cell suspension was counted as a uniform cell suspension. The cell density was adjusted to 1500 cells/well in a medium containing 10% serum, and re-inoculated into 96 cells. In a well cell culture plate, a culture volume of 200 μL was cultured at 37 ° C in a 5% CO ₂ incubator; the culture was carried out for 24 hours and used for the experiment.

化合物作用Compound action

将培养24小时的细胞从培养箱中取出，吸出孔板中培养液，每孔加入200μL用含10％胎牛血清的培养基配制好的化合物溶液，每个浓度5个平行，设置DMSO作为阴性对照，于37℃，5％CO2培养培养72小时进行CCK-8检测。The cells cultured for 24 hours were taken out from the incubator, and the culture medium in the well plate was aspirated, and 200 μL of a compound solution prepared in a medium containing 10% fetal bovine serum was added to each well, and each concentration was 5 parallel, and DMSO was set as a negative. Control, CCK-8 detection was carried out by culturing at 37 ° C, 5% CO 2 culture for 72 hours.

CCK-8检测CCK-8 detection

取无血清培养基和CCK-8溶液，按照10:1的比例配制成CCK-8工作液(该过程需要避光)。Take serum-free medium and CCK-8 solution and prepare CCK-8 working solution in a ratio of 10:1 (this process needs to be protected from light).

将培养72小时的细胞从培养箱中取出，吸出孔板中培养液，每孔加入120μLCCK-8工作液，同时在无细胞的孔板中加入120μLCCK-8工作液，作为空白对照，37℃，5％CO2培养箱培养1小时(该过程需要避光)。The cells cultured for 72 hours were taken out from the incubator, the culture medium in the well plate was aspirated, 120 μL of LCCK-8 working solution was added to each well, and 120 μL of LCCK-8 working solution was added to the cell-free well plate as a blank control at 37 ° C. Incubate for 1 hour in a 5% CO2 incubator (this process needs to be protected from light).

从培养箱中取出孔板，每孔吸取100μL溶液到新的96孔板中，于450nm读取吸光度(该过程需要避光)。The well plates were removed from the incubator, and 100 μL of each solution was pipetted into a new 96-well plate, and the absorbance was read at 450 nm (this process needs to be protected from light).

数据处理：data processing:

Tx：化合物作用72小时后，CCK-8测得的吸光度Tx: absorbance measured by CCK-8 after 72 hours of compound action

C：阴性对照孔培养72小时，CCK-8测得的吸光度C: Negative control wells were cultured for 72 hours, and the absorbance measured by CCK-8

B：空白对照孔，CCK-8测得的吸光度B: blank control well, absorbance measured by CCK-8

在上述测定中运行实施例制备的化合物1～19，试验结果见表3，其中测定的各化合物的一次或多次运行的最高IC50按照说明分类，表3中：The compounds 1 to 19 prepared in the examples were run in the above assay. The test results are shown in Table 3, wherein the highest IC50 of one or more runs of each compound determined was classified according to the description, in Table 3:

“+”表示该化合物在癌细胞中的IC50测定大于10uM；"+" means that the IC50 of the compound in cancer cells is greater than 10 uM;

“++”表示该化合物在癌细胞中的IC50测定小于10uM； "++" means that the IC50 of the compound in cancer cells is less than 10 uM;

表3化合物对不同肝癌细胞的抑制活性Table 3 compounds inhibiting the activity of different liver cancer cells

化合物Compound	HepG2HepG2	Huh-7Huh-7	Li-7Li-7	Hep3BHep3B
11	++	++	++	++
22	++	++	++	++
33	++	++	++	++
44	++	++	++	++
55	++	++	++	++
66	++	++	++	++
77	++	++	++	++
88	++	++	++	++
99	++	++	++	++
1010	++	++	++	++
1111	++	++	++	++
1212	++++	++	++	++
1313	++++	++	++++	++++
1414	++++	++	++++	++++
1515	++++	++	++++	++++
1616	++++	++	++	++
1717	++	++	++	++
1818	++	++	++	++
1919	++	++	++	++

试验表明，本发明化合物1～19对不同的肝癌细胞(HepG2、Huh-7、Li-7、Hep3B)均具有良好的抑制活性。Tests have shown that the compounds 1 to 19 of the present invention have good inhibitory activities against different liver cancer cells (HepG2, Huh-7, Li-7, Hep3B).

综上所述，本发明公开的式Ⅰ所示的新化合物，表现出了良好的去乙酰化酶抑制活性，为临床治疗与组蛋白去乙酰化酶活性异常相关的疾病提供了一种新的药用可能；同时，本发明新化合物的制备方法，具有步骤少、操作简便、安全环保、收率高等优点，非常适合产业上的应用。 In summary, the novel compound of the formula I disclosed in the present invention exhibits good deacetylase inhibitory activity, and provides a novel treatment for diseases associated with abnormal histone deacetylase activity in clinical treatment. At the same time, the preparation method of the novel compound of the invention has the advantages of few steps, simple operation, safety and environmental protection, high yield, and the like, and is very suitable for industrial application.

Claims

式Ⅰ所示的吡咯酰胺类化合物或其晶型、药学上可接受的盐、水合物或溶剂合物：A pyrrolamide compound of the formula I or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

其中，among them,

R₁选自氢、羟基、氰基、卤素、羧基、C₁～C₆的烷基、C₁～C₆的烷氧基、C₂～C₆的酰胺基、C₂～C₆的氨酰基、C₃～C₆的杂环基、C₃～C₆的杂环烯基或苯氧基；R _{1 is} selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ amide, C ₂ -C ₆ ammonia An acyl group, a C ₃ -C ₆ heterocyclic group, a C ₃ -C ₆ heterocycloalkenyl group or a phenoxy group;

R₂选自氢、羟基、氰基、卤素、羧基、C₁～C₆的烷基、C₁～C₆的烷氧基、C₂～C₆的酰胺基、C₂～C₆的氨酰基、C₃～C₆的杂环基、C₃～C₆的杂环烯基、苯氧基、苯基或取代的苯基；R _{2 is} selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ amide, C ₂ -C ₆ ammonia An acyl group, a C ₃ -C ₆ heterocyclic group, a C ₃ -C ₆ heterocycloalkenyl group, a phenoxy group, a phenyl group or a substituted phenyl group;

R₃选自羟基、氨基取代的苯基、巯基或环氧酮基团；R _{3 is} selected from a hydroxyl group, an amino-substituted phenyl group, a fluorenyl group or an epoxy ketone group;

X选自
基团，m＝0、1、2或3，n＝0、1或2。X is selected from
A group, m = 0, 1, 2 or 3, n = 0, 1 or 2.
根据权利要求1所述的吡咯酰胺类化合物或其晶型、药学上可接受的盐、水合物或溶剂合物，其特征在于：The pyrrole amide compound according to claim 1, or a crystalline form thereof, a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized by:

R₁选自氢、羟基、氰基、氟、氯、溴、羧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊烷基、己烷基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊烷氧基、己烷氧基、甲酰胺基、乙酰氨基、正丙酰胺基、异丙酰胺基、正丁酰胺基、异丁酰胺基、叔丁酰胺基、戊烷酰胺基、己烷酰胺基、甲氨酰基、乙氨酰基、正丙氨酰基、异丙氨酰基、正丁氨酰基、异丁氨酰基、叔丁氨酰基、戊氨酰基、己氨酰基、C₃的氮杂环基、C₄的氮杂环基、C₅的氮杂环基、C₆的氮杂环基、C₃的氮杂环烯基、C₄的氮杂环烯基、C₅的氮杂环烯基、C₆的氮杂环烯基或苯氧基；R _{1 is} selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentylene, hexyl Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, Acetylamino, n-propionamido, isopropylamide, n-butyryl, isobutyryl, t-butyryl, pentane amide, hexane amide, carbamoyl, acetylyl, n-alanyl , isopropylamino, n-butyryl, isobutyryl, tert-butyryl, pentyl, hexyl, aziridine of C ₃ , azacyclic of C ₄ , aza of C ₅ a cyclic group, a nitrogen heterocyclic group of C _{6 ,} an azacycloalkenyl group of C _{3 ,} an azacycloalkenyl group of C _{4 ,} an azacycloalkenyl group of C _{5 ,} an azacycloalkenyl group of C ₆ or a phenoxy group ;

R₂选自氢、羟基、氰基、氟、氯、溴、羧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊烷基、己烷基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊烷氧基、己烷氧基、甲酰胺基、乙酰氨基、正丙酰胺基、异丙酰胺基、正丁酰胺基、异丁酰胺基、叔丁酰胺基、戊烷酰胺基、己烷酰胺基、甲氨酰基、乙氨酰基、正丙氨酰基、异丙氨酰基、正丁氨酰基、异丁氨酰基、叔丁氨酰基、戊氨酰基、己氨酰基、C₃的氮杂环基、C₄的氮杂环基、C₅的氮杂环基、C₆的氮杂环基、C₃的氮杂环烯基、C₄的氮杂环烯基、C₅的氮杂环烯基、C₆的氮杂环烯基、苯氧基、苯基或取代的苯基；R _{2 is} selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentylene, hexyl Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, Acetylamino, n-propionamido, isopropylamide, n-butyryl, isobutyryl, t-butyryl, pentane amide, hexane amide, carbamoyl, acetylyl, n-alanyl , isopropylamino, n-butyryl, isobutyryl, tert-butyryl, pentyl, hexyl, aziridine of C ₃ , azacyclic of C ₄ , aza of C ₅ a cyclic group, a nitrogen heterocyclic group of C _{6 ,} a nitrogen heterocycloalkenyl group of C ₃ , azacycloheteroyl group of C ₄ , azacycloheteroyl group of C ₅ , azacycloalkenyl group of C ₆ , phenoxy group Phenyl or substituted phenyl;

R₁与R₂不同时为氢；When R _{1 is} different from R _{2 ,} it is hydrogen;

R₃选自羟基、氨基取代的苯基或巯基；R _{3 is} selected from a hydroxy group, an amino-substituted phenyl group or a fluorenyl group;

m＝1或2，n＝1或2。m=1 or 2, n=1 or 2.
根据权利要求1或2所述的吡咯酰胺类化合物或其晶型、药学上可接受的盐、水合物或溶剂合物，其特征在于：式Ⅰ所示化合物为：The pyrrole amide compound according to claim 1 or 2, or a crystalline form thereof, a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound of the formula I is:
一种制备式Ⅰ所示吡咯酰胺类化合物的方法，其特征在于：它的合成路线为：A method for preparing a pyrrole amide compound of the formula I, characterized in that the synthetic route is:

或者， Or,

R₁选自氢、羟基、氰基、卤素、羧基、C₁～C₆的烷基、C₁～C₆的烷氧基、C₂～C₆的酰胺基、C₂～C₆的氨酰基、C₃～C₆的杂环基、C₃～C₆的杂环烯基或苯氧基；R _{1 is} selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ amide, C ₂ -C ₆ ammonia An acyl group, a C ₃ -C ₆ heterocyclic group, a C ₃ -C ₆ heterocycloalkenyl group or a phenoxy group;

R₂选自氢、羟基、氰基、卤素、羧基、C₁～C₆的烷基、C₁～C₆的烷氧基、C₂～C₆的酰胺基、C₂～C₆的氨酰基、C₃～C₆的杂环基、C₃～C₆的杂环烯基、苯氧基、苯基或取代的苯基；R _{2 is} selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ amide, C ₂ -C ₆ ammonia An acyl group, a C ₃ -C ₆ heterocyclic group, a C ₃ -C ₆ heterocycloalkenyl group, a phenoxy group, a phenyl group or a substituted phenyl group;

R₅选自卤素；R _{5 is} selected from halogen;

X选自
基团，m＝0、1、2或3，n＝0、1或2；X is selected from
a group, m = 0, 1, 2 or 3, n = 0, 1 or 2;

包括以下步骤：Includes the following steps:

a、化合物IM-4、氢氧化锂和醚类溶剂/水的混合溶剂，于20℃～30℃搅拌反应1h～6h后，除去有机溶剂，加水稀释，调节pH＝3～6，析出固体，过滤，得到固体；对固体进行水洗、干燥，得到N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-甲酸；a, compound IM-4, lithium hydroxide and ether solvent / water mixed solvent, stirring reaction at 20 ° C ~ 30 ° C for 1h ~ 6h, remove the organic solvent, diluted with water, adjust the pH = 3 ~ 6, precipitate solid, Filtration to obtain a solid; washing the solid with water and drying to give N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid;

所述化合物IM-4与氢氧化锂的摩尔比为1：(1～10)；所述化合物IM-4与混合溶剂的质量体积比为1：(7～20)(m：v)；所述混合溶剂中，醚类溶剂与水的体积比为(1～2)：1；The molar ratio of the compound IM-4 to lithium hydroxide is 1: (1 to 10); the mass to volume ratio of the compound IM-4 to the mixed solvent is 1: (7 to 20) (m: v); In the mixed solvent, the volume ratio of the ether solvent to water is (1 to 2): 1;

b、0℃～5℃下，将步骤a的N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-甲酸溶解于卤烃类溶剂中，加入三氟乙酸，于20℃～30℃搅拌反应2h～12h后，得到反应液；对反应液进行浓缩，得到黄色油状物，即为化合物IM-3；b, N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid of step a is dissolved in a halogen hydrocarbon solvent at 0 ° C to 5 ° C, and trifluoroacetic acid is added at 20 ° C. After stirring at ～30°C for 2h~12h, the reaction liquid is obtained; the reaction liquid is concentrated to obtain a yellow oil, which is compound IM-3;

所述N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-甲酸、卤烃类溶剂与三氟乙酸的质量体积比1：(5～20)：(2～10)(m：v：v)；The mass-to-volume ratio of the N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid, halocarbon solvent and trifluoroacetic acid is 1: (5-20): (2-10) ( m:v:v);

c、步骤b的化合物IM-3、碳酸钠、芴氧甲酰氯和醚类溶剂/水的混合溶剂，于20℃～30℃搅拌反应12h～16h后，加水稀释，调节pH＝1～3，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到化合物IM-2；c. The compound IM-3 of the step b, the mixed solvent of sodium carbonate, decanoyl chloride and ether solvent/water is stirred at 20 ° C to 30 ° C for 12 h to 16 h, diluted with water, and adjusted to pH = 1 to 3, Extraction of the ester solvent, combining the organic phase, drying the organic phase, filtering, and concentrating to obtain the compound IM-2;

所述化合物IM-3、碳酸钠与芴氧甲酰氯的摩尔比为1：(1～5)：(0.9～1.5)；所述化合物IM-3与混合溶剂的质量体积比为1：(10～25)；所述混合溶剂中，醚类溶剂与水的体积比为(1～2)：1； The molar ratio of the compound IM-3, sodium carbonate and decanoyl chloride is 1: (1 to 5): (0.9 to 1.5); the mass to volume ratio of the compound IM-3 to the mixed solvent is 1: (10) ～25); in the mixed solvent, the volume ratio of the ether solvent to water is (1 to 2): 1;

d、步骤c的化合物IM-2、O-(四氢-2H-吡喃-2-基)羟基胺、2-(7-偶氮苯并三氮d, compound IM-2 of step c, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, 2-(7-azobenzotriazine)

唑)-N,N,N',N'-四甲基脲六氟磷酸酯、N,N-二异丙基乙胺和卤烃类溶剂，于25℃～30℃搅拌反应12h～16h后，加水稀释，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到粗品；粗品经柱层析纯化，得到化合物IM-1；Oxazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine and halogen hydrocarbon solvent, stirred at 25 ° C ~ 30 ° C for 12 h ~ 16 h , diluted with water, extracted with an ester solvent, the organic phase is combined, the organic phase is dried, filtered and concentrated to give a crude product; the crude product is purified by column chromatography to give compound IM-1;

所述化合物IM-2、O-(四氢-2H-吡喃-2-基)羟基胺、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯与N,N-二异丙基乙胺的摩尔比为1：(1～2)：(1～2)：(2～4)；所述化合物IM-2与卤烃类溶剂的质量体积比为1：(9～20)(m：v)；The compound IM-2, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, 2-(7-azobenzotriazole)-N,N,N',N'-four The molar ratio of methyl urea hexafluorophosphate to N,N-diisopropylethylamine is 1: (1 to 2): (1 to 2): (2 to 4); the compound IM-2 and halogen The mass-to-volume ratio of the hydrocarbon solvent is 1: (9 to 20) (m: v);

e、步骤d的化合物IM-1、哌啶和含氮类溶剂，于25℃～30℃搅拌反应4h～6h后，加水稀释，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到化合物IM；e, the compound IM-1 of the step d, the piperidine and the nitrogen-containing solvent are stirred at 25 ° C to 30 ° C for 4 h to 6 h, diluted with water, extracted with an ester solvent, and the organic phase is combined, and the organic phase is dried and filtered. Concentrated to obtain the compound IM;

所述化合物IM-1、哌啶与含氮类溶剂的质量体积比为1：(1～4)：(5～20)；The mass ratio of the compound IM-1, piperidine and the nitrogen-containing solvent is 1: (1 to 4): (5 to 20);

f、步骤e的化合物IM、三乙胺、
和卤烃类溶剂，于25℃～30℃搅拌反应1h～10h后，除去溶剂，得到粗品；粗品经柱层析纯化，得到化合物TM-1(a)；所述化合物IM、三乙胺、
的摩尔比为1：(1～5)：(1～2)；所述化合物IM与卤烃类溶剂的质量体积比为1：(50～100)(m：v)；f, compound IM of step e, triethylamine,
And a halogenated hydrocarbon solvent, after stirring at 25 ° C to 30 ° C for 1 h to 10 h, the solvent is removed to obtain a crude product; the crude product is purified by column chromatography to give the compound TM-1 (a); the compound IM, triethylamine,
The molar ratio is 1: (1 ~ 5): (1 ~ 2); the mass ratio of the compound IM to the halocarbon solvent is 1: (50 ~ 100) (m: v);

或者，or,

步骤e的化合物IM、三乙胺、
和卤烃类溶剂，于25℃～30℃搅拌反应1h～10h后，除去溶剂，得到粗品；粗品经柱层析纯化，得到化合物TM-1(b)；所述化合物IM、三乙胺、
的摩尔比为1：(1～5)：(1～2)；所述化合物IM与卤烃类溶剂的质量体积比为1：(50～100)(m：v)；Compound IM of step e, triethylamine,
And the halogenated hydrocarbon solvent is stirred at 25 ° C to 30 ° C for 1 h to 10 h, the solvent is removed to obtain a crude product; the crude product is purified by column chromatography to give the compound TM-1 (b); the compound IM, triethylamine,
The molar ratio is 1: (1 ~ 5): (1 ~ 2); the mass ratio of the compound IM to the halocarbon solvent is 1: (50 ~ 100) (m: v);

g、0℃～5℃下，将步骤f的化合物TM-1(a)溶解于卤烃类溶剂中，加入三氟乙酸，于25℃～30℃搅拌反应1h～12h后，除去溶剂，得到粗品；粗品经制备高效液相色谱纯化，得到化合物TM(a)；所述的化合物TM-1(a)、卤烃类溶剂、三氟乙酸的质量体积比为1：(50～100)：(10～50)(m：v：v)；g, the compound TM-1 (a) of the step f is dissolved in a halogen hydrocarbon solvent at 0 ° C to 5 ° C, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C to 30 ° C for 1 h to 12 h, and then the solvent is removed. The crude product is purified by preparative high performance liquid chromatography to obtain the compound TM(a); the mass ratio of the compound TM-1 (a), the halocarbon solvent and the trifluoroacetic acid is 1: (50-100): (10~50)(m:v:v);

或者，or,

0℃～5℃下，将步骤f的化合物TM-1(b)溶解于卤烃类溶剂中，加入三氟乙酸，于25℃～30℃搅拌反应1h～12h后，除去溶剂，得到粗品；粗品经制备高效液相色谱纯化，得到化合物TM(b)；所述的化合物TM-1(b)、卤烃类溶剂、三氟乙酸的质量体积比为1：(50～100)：(10～50)(m：v：v)。The compound TM-1 (b) of the step f is dissolved in a halogen hydrocarbon solvent at 0 ° C to 5 ° C, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C to 30 ° C for 1 h to 12 h, and then the solvent is removed to obtain a crude product; The crude product is purified by preparative high performance liquid chromatography to obtain the compound TM(b); the mass ratio of the compound TM-1 (b), the halocarbon solvent and the trifluoroacetic acid is 1: (50-100): (10) ~50) (m:v:v).
根据权利要求4所述的制备方法，其特征在于：包括以下步骤：The preparation method according to claim 4, comprising the steps of:

a、化合物IM-4、氢氧化锂和醚类溶剂/水的混合溶剂，于25℃搅拌反应2h后，除去有机溶剂，加水稀释，调节pH＝5，析出固体，过滤，得到固体；对固体进行水洗、干燥，得到N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-甲酸；a, compound IM-4, lithium hydroxide and ether solvent / water mixed solvent, stirred at 25 ° C for 2h, the organic solvent was removed, diluted with water, adjusted to pH = 5, precipitated solid, filtered to give a solid; Washing with water and drying to obtain N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid;

所述化合物IM-4与氢氧化锂的摩尔比为1：(4.5～5)；所述化合物IM-4与混合溶剂的质量体积比为1：(10～12)(m：v)；所述混合溶剂中，醚类溶剂与水的体积比为2：1；The molar ratio of the compound IM-4 to lithium hydroxide is 1: (4.5 to 5); the mass to volume ratio of the compound IM-4 to the mixed solvent is 1: (10 to 12) (m: v); In the mixed solvent, the volume ratio of the ether solvent to water is 2:1;

b、0℃下，将步骤a的N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-甲酸溶解于卤烃类溶剂中，加入三氟乙酸，于25℃搅拌反应2h后，得到反应液；对反应液进行浓缩，得到黄色油状物，即为化合物IM-3；b, N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid of step a is dissolved in a halogen hydrocarbon solvent at 0 ° C, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C for 2 h. After that, the reaction liquid is obtained; the reaction liquid is concentrated to obtain a yellow oil, which is the compound IM-3;

所述N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-甲酸、卤烃类溶剂与三氟乙酸的质量体积比1：10：(4～5)(m：v：v)；The mass-to-volume ratio of the N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid, halocarbon solvent and trifluoroacetic acid is 1:10:(4 to 5) (m:v: v);

c、步骤b的化合物IM-3、碳酸钠、芴氧甲酰氯和醚类溶剂/水的混合溶剂，于25℃搅拌反应12h～16h后，加水稀释，调节pH＝1，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到化合物IM-2；c. The compound IM-3 of the step b, the mixed solvent of the sodium carbonate, the decyloxycarbonyl chloride and the ether solvent/water is stirred at 25 ° C for 12 h to 16 h, diluted with water, adjusted to pH=1, and extracted with an ester solvent. The organic phase is combined, the organic phase is dried, filtered, and concentrated to give the compound IM-2;

所述化合物IM-3、碳酸钠与芴氧甲酰氯的摩尔比为1：3：1；所述化合物IM-3与混合溶剂的质量体积比为1：20；所述混合溶剂中，醚类溶剂与水的体积比为5：3；The molar ratio of the compound IM-3, sodium carbonate to decanoyl chloride is 1:3:1; the mass ratio of the compound IM-3 to the mixed solvent is 1:20; in the mixed solvent, the ether The volume ratio of solvent to water is 5:3;

d、步骤c的化合物IM-2、O-(四氢-2H-吡喃-2-基)羟基胺、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、N,N-二异丙基乙胺和卤烃类溶剂，于25℃搅拌反应12h～16h后，加水稀释，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到粗品；粗品经柱层析纯化，得到化合物IM-1；d, compound IM-2 of step c, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, 2-(7-azobenzotriazole)-N,N,N',N '-Tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine and halogen hydrocarbon solvent, stirred at 25 ° C for 12h ~ 16h, diluted with water, ester solvent extraction, combined organic phase, The organic phase is dried, filtered and concentrated to give a crude product; the crude product is purified by column chromatography to give compound IM-1;

所述化合物IM-2、O-(四氢-2H-吡喃-2-基)羟基胺、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯与N,N-二异丙基乙胺的摩尔比为1：1.1：1.2：3；所述化合物IM-2与卤烃类溶剂的质量体积比为1：(9～10)(m：v)；The compound IM-2, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, 2-(7-azobenzotriazole)-N,N,N',N'-four The molar ratio of methyl urea hexafluorophosphate to N,N-diisopropylethylamine is 1:1.1:1.2:3; the mass to volume ratio of the compound IM-2 to the halocarbon solvent is 1: (9) ～10)(m:v);

e、步骤d的化合物IM-1、哌啶和含氮类溶剂，于25℃搅拌反应4h～6h后，加水稀释，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到化合物IM； e, the compound IM-1 of the step d, the piperidine and the nitrogen-containing solvent are stirred at 25 ° C for 4 h to 6 h, diluted with water, extracted with an ester solvent, and the organic phase is combined, and the organic phase is dried, filtered and concentrated. Obtaining compound IM;

所述化合物IM-1、哌啶与含氮类溶剂的质量体积比为1：2：10；The mass ratio of the compound IM-1, piperidine and nitrogen-containing solvent is 1:2:10;

f、步骤e的化合物IM、三乙胺、
和卤烃类溶剂，于25℃搅拌反应2h后，除去溶剂，得到粗品；粗品经柱层析纯化，得到化合物TM-1(a)；所述化合物IM、三乙胺、
的摩尔比为1：1.4：(1～1.2)；所述化合物IM与卤烃类溶剂的质量体积比为1：80(m：v)；f, compound IM of step e, triethylamine,
After stirring with a halocarbon solvent for 2 h at 25 ° C, the solvent is removed to give a crude product; the crude product is purified by column chromatography to give compound TM-1 (a); the compound IM, triethylamine,
The molar ratio is 1:1.4: (1 to 1.2); the mass ratio of the compound IM to the halocarbon solvent is 1:80 (m:v);

或者，or,

步骤e的化合物IM、三乙胺、
和卤烃类溶剂，于25℃搅拌反应2h后，除去溶剂，得到粗品；粗品经柱层析纯化，得到化合物TM-1(b)；所述化合物IM、三乙胺、
的摩尔比为1：1.4：(1～1.2)；所述化合物IM与卤烃类溶剂的质量体积比为1：80(m：v)；Compound IM of step e, triethylamine,
After stirring with a halocarbon solvent for 2 h at 25 ° C, the solvent is removed to obtain a crude product; the crude product is purified by column chromatography to give the compound TM-1 (b); the compound IM, triethylamine,
The molar ratio is 1:1.4: (1 to 1.2); the mass ratio of the compound IM to the halocarbon solvent is 1:80 (m:v);

g、0℃下，将步骤f的化合物TM-1(a)溶解于卤烃类溶剂中，加入三氟乙酸，于25℃搅拌反应2h后，除去溶剂，得到粗品；粗品经制备高效液相色谱纯化，得到化合物TM(a)；所述的化合物TM-1(a)、卤烃类溶剂、三氟乙酸的质量体积比为1：(60～65)：25(m：v：v)；g, at 0 ° C, the compound TM-1 (a) of step f is dissolved in a halogen hydrocarbon solvent, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C for 2 h, then the solvent is removed to obtain a crude product; Purification by chromatography to obtain the compound TM (a); the mass ratio of the compound TM-1 (a), the halocarbon solvent, and the trifluoroacetic acid is 1: (60-65): 25 (m: v: v) ;

或者，or,

0℃下，将步骤f的化合物TM-1(b)溶解于卤烃类溶剂中，加入三氟乙酸，于25℃搅拌反应2h后，除去溶剂，得到粗品；粗品经制备高效液相色谱纯化，得到化合物TM(b)；所述的化合物TM-1(b)、卤烃类溶剂、三氟乙酸的质量体积比为1：(60～65)：25(m：v：v)。 The compound TM-1 (b) of the step f is dissolved in a halogen hydrocarbon solvent at 0 ° C, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C for 2 h, and then the solvent is removed to obtain a crude product; the crude product is purified by preparative high performance liquid chromatography. The compound TM (b) was obtained; the mass ratio of the compound TM-1 (b), the halocarbon solvent, and the trifluoroacetic acid was 1: (60 to 65): 25 (m: v: v).
根据权利要求4或5所述的制备方法，其特征在于：The preparation method according to claim 4 or 5, characterized in that:

R₁选自氢、羟基、氰基、氟、氯、溴、羧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊烷基、己烷基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊烷氧基、己烷氧基、甲酰胺基、乙酰氨基、正丙酰胺基、异丙酰胺基、正丁酰胺基、异丁酰胺基、叔丁酰胺基、戊烷酰胺基、己烷酰胺基、甲氨酰基、乙氨酰基、正丙氨酰基、异丙氨酰基、正丁氨酰基、异丁氨酰基、叔丁氨酰基、戊氨酰基、己氨酰基、C₃的氮杂环基、C₄的氮杂环基、C₅的氮杂环基、C₆的氮杂环基、C₃的氮杂环烯基、C₄的氮杂环烯基、C₅的氮杂环烯基、C₆的氮杂环烯基或苯氧基；R _{1 is} selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentylene, hexyl Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, Acetylamino, n-propionamido, isopropylamide, n-butyryl, isobutyryl, t-butyryl, pentane amide, hexane amide, carbamoyl, acetylyl, n-alanyl , isopropylamino, n-butyryl, isobutyryl, tert-butyryl, pentyl, hexyl, aziridine of C ₃ , azacyclic of C ₄ , aza of C ₅ a cyclic group, a nitrogen heterocyclic group of C _{6 ,} an azacycloalkenyl group of C _{3 ,} an azacycloalkenyl group of C _{4 ,} an azacycloalkenyl group of C _{5 ,} an azacycloalkenyl group of C ₆ or a phenoxy group ;

R₂选自氢、羟基、氰基、氟、氯、溴、羧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊烷基、己烷基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊烷氧基、己烷氧基、甲酰胺基、乙酰氨基、正丙酰胺基、异丙酰胺基、正丁酰胺基、异丁酰胺基、叔丁酰胺基、戊烷酰胺基、己烷酰胺基、甲氨酰基、乙氨酰基、正丙氨酰基、异丙氨酰基、正丁氨酰基、异丁氨酰基、叔丁氨酰基、戊氨酰基、己氨酰基、C₃的氮杂环基、C₄的氮杂环基、C₅的氮杂环基、C₆的氮杂环基、C₃的氮杂环烯基、C₄的氮杂环烯基、C₅的氮杂环烯基、C₆的氮杂环烯基、苯氧基、苯基或取代的苯基；R _{2 is} selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentylene, hexyl Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, Acetylamino, n-propionamido, isopropylamide, n-butyryl, isobutyryl, t-butyryl, pentane amide, hexane amide, carbamoyl, acetylyl, n-alanyl , isopropylamino, n-butyryl, isobutyryl, tert-butyryl, pentyl, hexyl, aziridine of C ₃ , azacyclic of C ₄ , aza of C ₅ a cyclic group, a nitrogen heterocyclic group of C _{6 ,} an azacycloalkenyl group of C _{3 ,} an azacycloalkenyl group of C _{4 ,} an azacycloalkenyl group of C _{5 ,} an azacycloalkenyl group of C ₆ , a phenoxy group Phenyl or substituted phenyl;

R₁与R₂不同时为氢；When R _{1 is} different from R _{2 ,} it is hydrogen;

R₅选自氟、氯、溴或碘；R _{5 is} selected from the group consisting of fluorine, chlorine, bromine or iodine;

m＝1或2，n＝1或2。m=1 or 2, n=1 or 2.
根据权利要求6所述的制备方法，其特征在于：所述
为：The preparation method according to claim 6, wherein:
for:
根据权利要求4或5所述的制备方法，其特征在于：步骤a～g中，所述醚类溶剂为四氢呋喃、***、叔丁基甲基醚、异丙醚、丁醚中的任意一种或多种；所述卤烃类溶剂为二氯甲烷、氯乙烷、二氯乙烷、三氯甲烷、四氯化碳中的任意一种或多种；所述酯类溶剂为乙酸乙酯、甲酸乙酯中的任意一种或多种；所述含氮类溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、吡啶中的任意一种或多种。The preparation method according to claim 4 or 5, wherein in the steps a to g, the ether solvent is any one or more of tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and dibutyl ether. The halocarbon solvent is any one or more of dichloromethane, ethyl chloride, dichloroethane, chloroform, carbon tetrachloride; the ester solvent is ethyl acetate, formic acid Any one or more of ethyl esters; and the nitrogen-containing solvent is any one or more of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and pyridine.
一种制备式Ⅰ所示吡咯酰胺类化合物的方法，其特征在于：它的合成路线为：A method for preparing a pyrrole amide compound of the formula I, characterized in that the synthetic route is:

其中，Boc代表叔丁氧羰基；TFA代表三氟乙酸；HATU代表2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；DIEA代表N,N-二异丙基乙胺；LiOH代表氢氧化锂；Wherein, Boc represents a tert-butoxycarbonyl group; TFA represents trifluoroacetic acid; and HATU represents 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DIEA stands for N,N-diisopropylethylamine; LiOH stands for lithium hydroxide;

R₁选自氢、羟基、氰基、卤素、羧基、C₁～C₆的烷基、C₁～C₆的烷氧基、C₂～C₆的酰胺基、C₂～C₆的氨酰基、C₃～C₆的杂环基、C₃～C₆的杂环烯基或苯氧基； R _{1 is} selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ amide, C ₂ -C ₆ ammonia An acyl group, a C ₃ -C ₆ heterocyclic group, a C ₃ -C ₆ heterocycloalkenyl group or a phenoxy group;

R₂选自氢、羟基、氰基、卤素、羧基、C₁～C₆的烷基、C₁～C₆的烷氧基、C₂～C₆的酰胺基、C₂～C₆的氨酰基、C₃～C₆的杂环基、C₃～C₆的杂环烯基、苯氧基、苯基或取代的苯基；R _{2 is} selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ amide, C ₂ -C ₆ ammonia An acyl group, a C ₃ -C ₆ heterocyclic group, a C ₃ -C ₆ heterocycloalkenyl group, a phenoxy group, a phenyl group or a substituted phenyl group;

R₅选自卤素；R _{5 is} selected from halogen;

包括以下步骤：Includes the following steps:

①、0℃～5℃下，将化合物IM-4溶解于卤烃类溶剂中，加入三氟乙酸，于20℃～30℃搅拌反应2h～12h，得到反应液；对反应液进行浓缩，得到黄色油状物，即为化合物IM-5；1. At 0 ° C to 5 ° C, the compound IM-4 is dissolved in a halogen hydrocarbon solvent, trifluoroacetic acid is added, and the reaction is stirred at 20 ° C to 30 ° C for 2 h to 12 h to obtain a reaction liquid; the reaction liquid is concentrated to obtain a yellow oil, which is the compound IM-5;

所述IM-4、卤烃类溶剂、三氟乙酸的质量体积比1：(5～20)：(2～10)；The mass to volume ratio of the IM-4, the halocarbon solvent, and the trifluoroacetic acid is 1: (5 to 20): (2 to 10);

②、步骤①的化合物IM-5、三乙胺、
和卤烃类溶剂，于25℃～30℃搅拌反应1h～10h后，加水淬灭反应，得到反应液；反应液用酯类溶剂萃取，合并有机相，用饱和食盐水洗涤，对有机相进行干燥、过滤、浓缩，得到粗品；粗品经柱层析纯化，得到化合物IM-6；2. Compound IM-5, triethylamine in step 1,
And the halogenated hydrocarbon solvent is stirred at 25 ° C to 30 ° C for 1 h to 10 h, and then quenched by adding water to obtain a reaction liquid; the reaction liquid is extracted with an ester solvent, and the organic phase is combined, washed with saturated brine, and the organic phase is subjected to an organic solvent. Drying, filtering, and concentrating to obtain a crude product; the crude product is purified by column chromatography to give compound IM-6;

所述化合物IM-5、三乙胺、
的摩尔比为1：(1～5)：(1～2)；所述化合物IM-5与卤烃类溶剂的质量体积比为1：(50～100)(m：v)；The compound IM-5, triethylamine,
The molar ratio is 1: (1 ~ 5): (1 ~ 2); the mass ratio of the compound IM-5 to the halocarbon solvent is 1: (50 ~ 100) (m: v);

③、步骤②的化合物IM-6、氢氧化锂和醚类溶剂/水的混合溶剂，于20℃～30℃搅拌反应10h～16h后，得到反应液；调节反应液的pH＝1～5，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到化合物IM-7；3. The compound IM-6 of the second step, a mixed solvent of lithium hydroxide and an ether solvent/water, and the reaction mixture is stirred at 20 to 30 ° C for 10 to 16 hours to obtain a reaction liquid; and the pH of the reaction solution is adjusted to 1 to 5, Extraction of the ester solvent, combining the organic phase, drying the organic phase, filtering, and concentrating to obtain the compound IM-7;

所述化合物IM-4与氢氧化锂的摩尔比为1：(1～10)；所述化合物IM-4与混合溶剂的质量体积比为1：(55～60)(m：v)；所述混合溶剂中，醚类溶剂与水的体积比为(1～5):1；The molar ratio of the compound IM-4 to lithium hydroxide is 1: (1 to 10); the mass to volume ratio of the compound IM-4 to the mixed solvent is 1: (55 to 60) (m: v); In the mixed solvent, the volume ratio of the ether solvent to water is (1 to 5): 1;

④、步骤③的化合物IM-7、1,2-二氨基苯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、N,N-二异丙基乙胺和卤烃类溶剂，于25℃～30℃搅拌反应12h～16h后，得到反应液；反应液用水稀释，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到粗品；粗品经柱层析纯化，得到化合物TM(c)；4. The compound of step 3, IM-7, 1,2-diaminobenzene, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate , N,N-diisopropylethylamine and a halogenated hydrocarbon solvent, after stirring at 25 ° C to 30 ° C for 12 h to 16 h, the reaction liquid is obtained; the reaction liquid is diluted with water, the ester solvent is extracted, and the organic phase is combined, organic The phase is dried, filtered and concentrated to obtain a crude product; the crude product is purified by column chromatography to give the compound TM(c);

所述化合物IM-7、1,2-二氨基苯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、N,N-二异丙基乙胺的摩尔比为1：(1～2)：(1～2)：(2～4)；所述化合物IM-7与卤烃类溶剂的质量体积比为1：(40～100)(m：v)。The compound IM-7, 1,2-diaminobenzene, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N, The molar ratio of N-diisopropylethylamine is 1: (1 to 2): (1 to 2): (2 to 4); the mass to volume ratio of the compound IM-7 to the halocarbon solvent is 1: (40 to 100) (m: v).
根据权利要求9所述的制备方法，其特征在于：包括以下步骤： The preparation method according to claim 9, comprising the steps of:

①、0℃下，将化合物IM-4溶解于卤烃类溶剂中，加入三氟乙酸，于25℃搅拌反应2h，得到反应液；对反应液进行浓缩，得到黄色油状物，即为化合物IM-5；1. At 0 ° C, the compound IM-4 was dissolved in a halogen hydrocarbon solvent, and trifluoroacetic acid was added thereto, and the reaction was stirred at 25 ° C for 2 hours to obtain a reaction liquid; the reaction liquid was concentrated to obtain a yellow oil, which was a compound IM. -5;

所述IM-4、卤烃类溶剂、三氟乙酸的质量体积比1：20：8；The mass ratio of the IM-4, the halocarbon solvent, and the trifluoroacetic acid is 1:20:8;

②、步骤①的化合物IM-5、三乙胺、
和卤烃类溶剂，于25℃搅拌反应2h后，加水淬灭反应，得到反应液；反应液用酯类溶剂萃取，合并有机相，用饱和食盐水洗涤，对有机相进行干燥、过滤、浓缩，得到粗品；粗品经柱层析纯化，得到化合物IM-6；2. Compound IM-5, triethylamine in step 1,
And the halogenated hydrocarbon solvent is stirred at 25 ° C for 2 h, and then quenched with water to obtain a reaction liquid; the reaction liquid is extracted with an ester solvent, and the organic phase is combined, washed with saturated brine, and the organic phase is dried, filtered and concentrated. , the crude product is obtained; the crude product is purified by column chromatography to obtain the compound IM-6;

所述化合物IM-5、三乙胺、
的摩尔比为1：(2.5～3)：(1.1～1.2)；所述化合物IM-5与卤烃类溶剂的质量体积比为1：(65～70)(m：v)；The compound IM-5, triethylamine,
The molar ratio is 1: (2.5 ~ 3): (1.1 ~ 1.2); the mass ratio of the compound IM-5 to the halocarbon solvent is 1: (65 ~ 70) (m: v);

③、步骤②的化合物IM-6、氢氧化锂和醚类溶剂/水的混合溶剂，于25℃搅拌反应12h～16h后，得到反应液；调节反应液的pH＝2，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到化合物IM-7；3. The compound IM-6 of step 2, a mixed solvent of lithium hydroxide and an ether solvent/water, and the reaction mixture is stirred at 25 ° C for 12 h to 16 h to obtain a reaction liquid; the pH of the reaction solution is adjusted to 2, and the ester solvent is extracted. The organic phase is combined, the organic phase is dried, filtered, and concentrated to give compound IM-7;

所述化合物IM-4与氢氧化锂的摩尔比为1：4.5；所述化合物IM-4与混合溶剂的质量体积比为1：(55～60)(m：v)；所述混合溶剂中，醚类溶剂与水的体积比为3:1；The molar ratio of the compound IM-4 to lithium hydroxide is 1:4.5; the mass to volume ratio of the compound IM-4 to the mixed solvent is 1:(55-60) (m:v); in the mixed solvent , the volume ratio of the ether solvent to water is 3:1;

④、步骤③的化合物IM-7、1,2-二氨基苯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、N,N-二异丙基乙胺和卤烃类溶剂，于25℃搅拌反应12h～16h后，得到反应液；反应液用水稀释，酯类溶剂萃取，合并有机相，对有机相进行干燥、过滤、浓缩，得到粗品；粗品经柱层析纯化，得到化合物TM(c)；4. The compound of step 3, IM-7, 1,2-diaminobenzene, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate , N, N-diisopropylethylamine and a halogenated hydrocarbon solvent, after stirring at 25 ° C for 12 h to 16 h, the reaction liquid is obtained; the reaction liquid is diluted with water, the ester solvent is extracted, the organic phase is combined, and the organic phase is dried. , filtration, concentration, to obtain a crude product; the crude product is purified by column chromatography to obtain the compound TM (c);

所述化合物IM-7、1,2-二氨基苯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、N,N-二异丙基乙胺的摩尔比为1：1.5：1.5：3；所述化合物IM-7与卤烃类溶剂的质量体积比为1：(40～45)(m：v)。The compound IM-7, 1,2-diaminobenzene, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N, The molar ratio of N-diisopropylethylamine is 1:1.5:1.5:3; the mass-to-volume ratio of the compound IM-7 to the halocarbon solvent is 1: (40 to 45) (m: v).
根据权利要求9或10所述的制备方法，其特征在于：The preparation method according to claim 9 or 10, characterized in that:

R₁选自氢、羟基、氰基、氟、氯、溴、羧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊烷基、己烷基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊烷氧基、己烷氧基、甲酰胺基、乙酰氨基、正丙酰胺基、异丙酰胺基、正丁酰胺基、异丁酰胺基、叔丁酰胺基、戊烷酰胺基、己烷酰胺基、甲氨酰基、乙氨酰基、正丙氨酰基、异丙氨酰基、正丁氨酰基、异丁氨酰基、叔丁氨酰基、戊氨酰基、己氨酰基、C₃的氮杂环基、C₄的氮杂环基、C₅的氮杂环基、C₆的氮杂环基、C₃的氮杂环烯基、C₄的氮杂环烯基、C₅的氮杂环烯基、C₆的氮杂环烯基或苯氧基；R _{1 is} selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentylene, hexyl Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, Acetylamino, n-propionamido, isopropylamide, n-butyryl, isobutyryl, t-butyryl, pentane amide, hexane amide, carbamoyl, acetylyl, n-alanyl , isopropylamino, n-butyryl, isobutyryl, tert-butyryl, pentyl, hexyl, aziridine of C ₃ , azacyclic of C ₄ , aza of C ₅ a cyclic group, a nitrogen heterocyclic group of C _{6 ,} a nitrogen heterocycloalkenyl group of C ₃ , azacycloheteroyl group of C ₄ , azacycloheteroyl group of C ₅ , azacycloalkenyl group of C ₆ or phenoxy group ;

R₂选自氢、羟基、氰基、氟、氯、溴、羧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊烷基、己烷基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊烷氧基、己烷氧基、甲酰胺基、乙酰氨基、正丙酰胺基、异丙酰胺基、正丁酰胺基、异丁酰胺基、叔丁酰胺基、戊烷酰胺基、己烷酰胺基、甲氨酰基、乙氨酰基、正丙氨酰基、异丙氨酰基、正丁氨酰基、异丁氨酰基、叔丁氨酰基、戊氨酰基、己氨酰基、C₃的氮杂环基、C₄的氮杂环基、C₅的氮杂环基、C₆的氮杂环基、C₃的氮杂环烯基、C₄的氮杂环烯基、C₅的氮杂环烯基、C₆的氮杂环烯基、苯氧基、苯基或取代的苯基；R _{2 is} selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentylene, hexyl Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, Acetylamino, n-propionamido, isopropylamide, n-butyryl, isobutyryl, t-butyryl, pentane amide, hexane amide, carbamoyl, acetylyl, n-alanyl , isopropylamino, n-butyryl, isobutyryl, tert-butyryl, pentyl, hexyl, aziridine of C ₃ , azacyclic of C ₄ , aza of C ₅ a cyclic group, a nitrogen heterocyclic group of C _{6 ,} an azacycloalkenyl group of C _{3 ,} an azacycloalkenyl group of C _{4 ,} an azacycloalkenyl group of C _{5 ,} an azacycloalkenyl group of C ₆ , a phenoxy group Phenyl or substituted phenyl;

R₁与R₂不同时为氢；When R _{1 is} different from R _{2 ,} it is hydrogen;

R₅选自氟、氯、溴或碘。R _{5 is} selected from the group consisting of fluorine, chlorine, bromine or iodine.
根据权利要求9或10所述的制备方法，其特征在于：所述
为：The preparation method according to claim 9 or 10, wherein:
for:
根据权利要求9或10所述的制备方法，其特征在于：步骤①～④中，所述卤烃类溶剂为二氯甲烷、氯乙烷、二氯乙烷、三氯甲烷、四氯化碳中的任意一种或多种；所述酯类溶剂为乙酸乙酯、甲酸乙酯中的任意一种或多种；所述醚类溶剂为四氢呋喃、***、叔丁基甲基醚、异丙醚、丁醚中的任意一种或多种。The preparation method according to claim 9 or 10, wherein in the steps 1 to 4, the halogen hydrocarbon solvent is dichloromethane, ethyl chloride, dichloroethane, chloroform or carbon tetrachloride. Any one or more of the solvent; the ester solvent is any one or more of ethyl acetate and ethyl formate; the ether solvent is tetrahydrofuran, diethyl ether, tert-butyl methyl ether, isopropyl ether, Any one or more of butyl ether.
权利要求1～3任意一项所述的吡咯酰胺类化合物或其晶型、药学上可接受的盐、水合物或溶剂合物，在制备组蛋白去乙酰化酶抑制剂类药物中的用途。 The use of the pyrrole amide compound according to any one of claims 1 to 3, or a crystalline form thereof, a pharmaceutically acceptable salt, a hydrate or a solvate thereof for producing a histone deacetylase inhibitor drug.
根据权利要求14所述的用途，其特征在于：所述组蛋白去乙酰化酶抑制剂类药物是治疗由组蛋白去乙酰化酶活性异常所导致的疾病的药物。The use according to claim 14, wherein the histone deacetylase inhibitor drug is a drug for treating a disease caused by abnormal histone deacetylase activity.
根据权利要求15所述的用途，其特征在于：所述疾病是细胞增殖疾病、自身免疫疾病、炎症、神经变性疾病或病毒性疾病中的任意一种或多种。The use according to claim 15, wherein the disease is any one or more of a cell proliferation disease, an autoimmune disease, an inflammation, a neurodegenerative disease, or a viral disease.
根据权利要求16所述的用途，其特征在于：所述疾病为癌症。The use according to claim 16, wherein the disease is cancer.
一种抑制组蛋白去乙酰化酶活性的药物组合物，其特征在于：它是以权利要求1～3任意一项所述的吡咯酰胺类化合物或其晶型、药学上可接受的盐、水合物或溶剂合物为活性成分，加上药学上常用的辅料或辅助性成分制备得到的制剂。A pharmaceutical composition for inhibiting histone deacetylase activity, which is characterized in that it is a pyrrole amide compound according to any one of claims 1 to 3 or a crystal form thereof, a pharmaceutically acceptable salt, or a hydrated product. The preparation or the solvate is an active ingredient, and a preparation prepared by adding a pharmaceutically acceptable adjuvant or auxiliary ingredient.
根据权利要求18所述的药物组合物，其特征在于：所述的制剂包括口服给药制剂、舌下给药制剂、颊给药制剂、透皮吸收制剂或注射制剂。 The pharmaceutical composition according to claim 18, wherein the preparation comprises an orally administered preparation, a sublingual preparation, a buccal preparation, a transdermal absorption preparation or an injection preparation.